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CN116057057A - Combinations of α2-adrenergic receptor subtype C (α-2C) antagonists and TASK1/3 channel blockers for the treatment of sleep apnea - Google Patents

Combinations of α2-adrenergic receptor subtype C (α-2C) antagonists and TASK1/3 channel blockers for the treatment of sleep apnea Download PDF

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CN116057057A
CN116057057A CN202180054597.6A CN202180054597A CN116057057A CN 116057057 A CN116057057 A CN 116057057A CN 202180054597 A CN202180054597 A CN 202180054597A CN 116057057 A CN116057057 A CN 116057057A
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imidazo
methanone
diazabicyclo
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M·德尔贝克
M·哈恩
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Abstract

本发明涉及TASK‑1和TASK‑3通道的选择性阻断剂，特别是式(II)的取代的咪唑并[1，2‑a]嘧啶和取代的咪唑并[1，2‑a]吡啶衍生物，与α2‑肾上腺素受体亚型C(α‑2C)拮抗剂，特别是式(I)的取代的杂环甲酰胺的结合物，其用于治疗和/或预防睡眠相关的呼吸障碍，优选阻塞性和中枢性睡眠呼吸暂停和打鼾。The present invention relates to selective blockers of TASK-1 and TASK-3 channels, particularly substituted imidazo[1,2-a]pyrimidines and substituted imidazo[1,2-a]pyridines of formula (II) Derivatives, conjugates with α2-adrenergic receptor subtype C (α-2C) antagonists, in particular substituted heterocyclic carboxamides of formula (I), for the treatment and/or prevention of sleep-related respiration Disorders, preferably obstructive and central sleep apnea and snoring.

Description

Conjugates of alpha 2-adrenoceptor subtype C (alpha-2C) antagonists and TASK1/3 channel blockers for the treatment of sleep apnea
The present invention relates to selective blockers of TASK-1 and TASK-3 channels, in particular substituted imidazo [1,2-a ] pyrimidine and substituted imidazo [1,2-a ] pyridine derivatives of formula (II), in combination with an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist, in particular a substituted heterocyclic carboxamide of formula (I), for use in the treatment and/or prevention of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
Background
Obstructive Sleep Apnea (OSA) is a sleep-related respiratory disorder characterized by recurrent episodes of upper airway obstruction. The interaction between the two opposing forces ensures the patency of the upper respiratory tract upon inhalation. The dilating effect of the upper airway muscles counteracts the negative pressure in the lumen, causing the lumen to contract. Active contraction of the diaphragm and other ancillary respiratory muscles creates negative pressure in the respiratory tract, thus constituting the driving force for breathing. The stability of the upper respiratory tract is essentially dependent on the coordinated and contractile characteristics of the upper respiratory tract's dilated muscles.
Since some of the upper airway dilated muscles have reduced mobility, it is thought that the upper airway collapse of OSA occurs at the beginning of sleep, with the result that the physiologically weak (vulnerable) airway cannot be maintained open. However, certain upper airway distending muscles, including the genioglossus muscle (which is the most important of the upper airway distending muscles and is innervated by hypoglossal nerves), can enhance activity during sleep in response to respiratory stimuli, potentially counteracting some of these changes at the beginning of sleep. OSA patients have been observed to have an interval of no apnea during which the genioglossus muscle activity is increased by only 25-40% compared to sleep stages with frequent obstructive apneas (Jordan AS, white DP, loyl et al, airway dilator muscle activityand lung volume during stable breathinginobstructive sleep apea. Sleep2009, 32 (3): 361-8). Norepinephrine is one of the most potent neuromodulators of sublingual motor neuron activity (Horner r.l. Neuroregulation of hypoglossalmotoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196). It is believed that reduced noradrenergic actuation results in a reduced excitatory sleep dependence of the sublingual motor neurons, resulting in reduced activity of the upper airway dilator muscles, and in particular of the lingual muscles.
The α2c adrenergic receptors regulate norepinephrine released by central noradrenergic neurons and are autoreceptors involved in presynaptic feedback inhibition of norepinephrine (Hein l.et al Two functionally distinct alpha2-adrenergic receptorsregulate sympathetic neurotransmission Nature 1999, 402 (6758): 181-184). Increased motor neuron activity of the hypoglossal nerve through antagonism of the alpha 2c adrenergic receptor stabilizes the upper respiratory tract and protects them from collapse and obstruction. In addition, snoring can be inhibited by a mechanism that stabilizes the upper respiratory tract.
For mere snoring, the upper respiratory tract is not obstructed. The flow rate of inhaled and exhaled air increases due to the narrowing of the upper respiratory tract. This, together with the relaxed muscles, causes the soft tissues of the mouth and throat to vibrate in the airflow. Such slight vibrations can produce typical snoring.
Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This results in an increase in airway resistance and thus in an increase in work of breathing as the intrathoracic pressure fluctuates significantly. The development of negative intrathoracic pressure during inspiration can reach values resulting from complete airway obstruction in OSA. The pathophysiological effects on heart, blood circulation and sleep quality are the same as those of obstructive sleep apnea. Its pathogenesis may also be the same as OSA. Obstructive snoring is generally a precursor to OSA (HollandtJ.H. et al, upperairway resistan ce syndrome (UARS) -obstructive snoring.HNO 2000, 48 (8): 628-634).
Central Sleep Apnea (CSA) is caused by a disturbance of brain function or impaired respiratory regulation. CSA is characterized by a lack of driving force for breathing during sleep, resulting in repeated periods of inadequate or absent ventilation and poor gas exchange. CSA has several manifestations. These include high altitude induced periodic breathing, idiopathic CSA (ICSA), narcotic induced central apneas, obesity-hypoventilation syndrome (OHS), and Cheyne-Stokes respiration (CSB). Although the precise precipitation mechanisms involved in various types of CSAs may vary widely, unstable ventilatory drive during sleep is a major potential feature (eckertd.j. Et al Central sleep apnea: pathophysiology and treatment.chest 2007, 131 (2): 595-607).
US 2018/0235934 A1 describes a method of using an agent for promoting the excitability of sublingual motor neurons in the treatment of diseases such as obstructive sleep apnea. As agents that promote the excitability of sublingual motor neurons, de-inhibitors and/or agonists of central adrenal neurons are described. In some embodiments, the de-inhibitor of central noradrenergic neurons is an alpha 2-adrenergic receptor antagonist, such as a yohimbine (yohimbine) or an alpha 2-adrenergic receptor subtype a (alpha-2A) antagonist or an alpha 2-adrenergic receptor subtype C (alpha-2C) antagonist. The alpha 2-adrenoreceptor antagonist is selected from the group consisting of atipamazole (atipamazole), MK-912, RS-79948, RX 821002, [3H ] 2-methoxy-imidazolyl (idazoxan) and JP-1302.
The α2c adrenergic receptors belong to the G protein-coupled receptor family. In addition to the presence of different α1-adrenoreceptors, there are three different α2-adrenoreceptor subtypes (α2a, α2b and α2c). They are involved in the mediation of several different physiological actions in different tissues when stimulated by endogenous catecholamines (epinephrine, norepinephrine) derived from synapses or obtained via blood. The α2 adrenergic receptors play an important physiological role, mainly in the cardiovascular system and central nervous system. The α2a and a2C adrenoreceptors are the primary autoreceptors involved in presynaptic feedback inhibition of norepinephrine in the central nervous system. Norepinephrine is more potent and avid at the α2c-adrenergic receptor than at the α2a-adrenergic receptor. The α2c-adrenoceptors inhibit the release of norepinephrine at low endogenous concentrations of norepinephrine, whereas the α2a-adrenoceptors inhibit the release of norepinephrine at high endogenous concentrations of norepinephrine (Uys m.m. et al therapeutic Potential of SelectivelyTargeting the α2c-Adrenoceptor in Cognition, compression, and schizophrina-New Developments and Future perselective.
Another mechanism for maintaining airway patency relies on negative pressure sensitive nerve endings/mechanoreceptors located in the pharyngeal mucosa. When small negative pressures are detected during the respiratory cycle, these receptors produce excitatory motor output to the genioglossus muscle via negative pressure reflection.
Genioglossus muscle plays a decisive role in the pathogenesis of obstructive sleep apnea. In the sense of the dilatation compensation mechanism, the activity of this muscle increases with decreasing pressure in the pharynx. Through neurohypoglossal innervation, it drives the tongue forward and downward, widening the pharyngeal airway [ Verse et al, somnologice 3, 14-20 (1999) ]. The tone of the dilated muscles of the upper respiratory tract is regulated inter alia by mechanoreceptors/stretch receptors in the nasal cavity/pharynx [ Bouillette et al j.appl. Physiol. Respir. Environ. Exerc. Physiol.46, 772-779 (1979). In sleeping patients suffering from severe sleep apnea, an additional decrease in genioglossus muscle activity can be observed under local anesthesia of the upper respiratory tract [ Berry et al, am. J. Respir. Crit. Care med.156, 127-132 (1997) ].
In the sleep apnea model in anesthetized pigs, intranasal administration of potassium channel blockers blocking TASK-1 channels in the nanomolar range resulted in inhibition of the collapsible nature of the pharyngeal respiratory musculature and sensitization of the negative pressure reflex of the upper respiratory tract. Intranasal administration of potassium channel blockers is presumed to depolarize mechanoreceptors in the upper respiratory tract and, through activation of negative pressure reflex, to increase the activity of the upper respiratory tract musculature, thereby stabilizing the upper respiratory tract and preventing collapse. Due to this stabilizing effect of the upper respiratory tract, TASK channel blockade can be very important for obstructive sleep apnea and snoring. [ Wirth et al, sleep 36, 699-708 (2013); kiper et al, pflugers arc.467, 1081-1090 (2015) ].
Of particular interest is TASK (TWIK-related acid sensitivity K + Channel) and TASK-3 (KCNK 9 or K2P9.1). Functionally, these channels are characterized by, during maintenance of voltage independent dynamicsThey have a "leakage" or "background" flow through them, and they respond to a variety of physiological and pathological effects by increasing or decreasing their activity. TASK channels are characterized by a sensitive response to extracellular pH changes: at acidic pH, channels are inhibited, while at basic pH they are activated.
The TASK-1 and TASK-3 channels also play a role in respiratory regulation. Both channels are expressed in the respiratory neurons of the respiratory centre of the brain stem, in particular in neurons producing respiratory rhythms (with the front
Figure BDA0004107514540000041
Complex abdominal respiratory), and in noradrenergic blue spots, and in serotonergic neurons of the center slit nucleus (serotonergic neuron). Because of the pH dependence, the TASK channel has here the function of transforming extracellular pH changes into receptors for the corresponding cell signals [ Bayliss et al, pflugers Arch.467, 917-929 (2015)]. TASK-1 and TASK-3 are also expressed in the carotid artery, the carotid balloon, a peripheral chemoreceptor, which measures the pH, O of blood 2 And CO 2 Content and signal to the respiratory center in the brain stem to regulate respiration. TASK-1 knockout mice have been shown to have reduced ventilation response (increased respiratory rate and tidal volume) to hypoxia and normoxic hypercarbonemia [ Trapp et al, j. Neurosci.28, 8844-8850 (2008)]. Furthermore, TASK-1 and TASK-3 channels have been shown to play an important role in keeping the upper respiratory tract open in motor neurons of the hypoglossal nerve (cranial nerve XII) [ Berg et al, J.Neurosci.24, 6693-6702 (2004)]。
Arylpiperazines as alpha 2-adrenoreceptor subtype C (alpha 2C) antagonists, processes for their preparation and their use as pharmaceuticals are known from WO 03/08082866 A1, which discloses that the compounds are useful for the treatment of diseases such as diseases caused by stress conduction (produced), parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, tourette's syndrome, blepharospasm or other localized dystonias, temporal lobe epilepsy with psychosis, drug-induced psychosis, huntington's disease, diseases caused by fluctuations in sex hormone levels, panic disorder, alzheimer's disease or mild cognitive impairment. There is no disclosure of the use of these compounds in the treatment of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
The gold standard treatment for OSA patients is currently Continuous Positive Airway Pressure (CPAP). The positive airflow pressure generated by the airflow turbo pump splint opens the upper airway, reversing all the causes that may lead to throat collapse, thereby preventing hypopnea, apnea, and hypopnea. Unfortunately, up to 50% of all OSA patients are unable to tolerate CPAP for long periods (M.Kohler, D.Smith, V.Tippett et al, thorax 2010 65 (9): 829-32:Predictors of long-term compliance with continuous positive airwaypressure). Thus, there remains a need to find effective therapeutic agents to treat and/or prevent sleep-related respiratory diseases, such as obstructive sleep apnea. It is therefore an object of the present invention to provide an effective therapeutic agent for the treatment and/or prevention of sleep-related respiratory diseases such as obstructive sleep apnea, central sleep apnea and snoring.
Surprisingly, it has now been found that a combination of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist with a TASK1/3 channel blocker inhibits the collapsible upper respiratory tract and has an improved efficacy compared to each individual treatment and is therefore suitable for the preparation of a medicament for the treatment and/or prophylaxis of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring. It has been found that the synergistic effect of a combination of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist and a TASK1/3 channel blocker allows for lower doses per treatment than each treatment alone.
The present invention relates to a combination of a compound of formula (I) and a compound of formula (II), and salts, solvates and solvates of salts thereof
Figure BDA0004107514540000051
Wherein the method comprises the steps of
X represents S, N or O;
y represents N, S or O, and the total number of the catalyst is,
wherein the method comprises the steps of
If X represents S, Y represents N;
z represents a group of compounds C, O, N,
wherein the method comprises the steps of
If X represents N and Y represents N, Z represents O;
R 1 represents a 5-or 6-membered heteroaryl or phenyl group,
wherein the 5-or 6-membered heteroaryl group may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -substituent substitution of alkoxy and halogen;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) The alkoxy groups may in turn be up to trisubstituted by halogen,
wherein the phenyl groups may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 3 -C 5 ) Cycloalkyl, (C) 1 -C 4 ) -substitution of substituents for alkoxy, cyano, hydroxy and halogen;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 2 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
or (b)
And R is R 2 The carbon atoms to which they are attached together form a (C 3 -C 4 ) A cycloalkyl ring, which is a ring-shaped member,
R 3 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 4 represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) -cycloalkyl, phenyl or halogen;
wherein%C 1 -C 4 ) Alkyl may in turn be up to trisubstituted by halogen, and phenyl may in turn be substituted by halogen,
R 5 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -an alkoxy group or a halogen group,
R 6 a group of formula a), b), c), d), e), f) or g)
Figure BDA0004107514540000061
Wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) -a cyclic alkoxy group or a phenyl group,
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) A cycloalkoxy group and may be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl may in turn be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and may be up to two times by halogen,
wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl groups in turn may be mono-or di-substituted by halogen,
wherein (C) 3 -C 4 ) The cycloalkoxy groups may in turn be up to disubstituted by halogen,
wherein R is 8 Represents hydrogen or fluorine, and is preferably selected from the group consisting of,
wherein R is 9 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -alkoxy or halogen;
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 1 -C 4 ) -an alkoxy group substituted by at least one amino group,
n represents 0 or 1, and the number of the n is,
m represents 0, 1 or 2,
p represents 0, 1 or 2
q represents 0, 1 or 2,
Figure BDA0004107514540000071
wherein the method comprises the steps of
Ring Q represents a piperazine or diazabicyclo system of the formula
Figure BDA0004107514540000081
Represents a bond to an adjacent CHR'2 group and represents a bond to a carbonyl group,
W 1 、W 2 or W 3 Represents a group of compounds represented by CH or N,
R’ 1 represents halogen, cyano, (C) 1 -C 4 ) -alkyl, cyclopropyl or cyclobutyl
Wherein (C) 1 -C 4 ) Alkyl groups can be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl groups can be up to disubstituted by fluorine,
and is also provided with
R’ 2 Representative (C) 4 -C 6 ) Cycloalkyl wherein ring CH 2 The group may be replaced by an-O-group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or (c) or pyrrolyl of the formula (d), (e), (f) or (g),
Figure BDA0004107514540000091
wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine, chlorine, bromine or methyl,
R’ 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) -alkoxy groups, wherein (C 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents hydrogen, (C) 1 -C 3 ) -alkoxy, cyclobutoxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono- (C) 1 -C 3 ) -alkylamino, di- (C) 1 -C 3 ) -alkylamino or (C) 1 -C 3 ) Alkylthio ((C) 1 -C 3 )-alkylsulfanyl)，
Wherein (C) 1 -C 3 ) The alkoxy group may be up to trisubstituted by fluorine,
R 7 represents hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl, cyclopropyl or (C) 1 -C 3 ) -alkoxy groups
Wherein (C) 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R 9 represents hydrogen, (C) 1 -C 3 ) -alkyl or amino
and
Wherein in the sub-formula (d)
Y represents O, S or N (CH) 3 )，
Wherein in the sub-formulae (e) and (f)
Y represents O or S, and the like,
or (b)
R’ 2 represents-OR 10 or-NR 11 R 12 A group in which
R 10 Representative (C) 1 -C 6 ) -alkyl, (C) 4 -C 6 ) Cycloalkyl or [ (C) 3 -C 6 ) Cycloalkyl radicals]A methyl group,
R 11 represents hydrogen or (C) 1 -C 3 ) -alkyl group
and
R 12 Representative (C) 1 -C 6 ) -alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl or benzyl, 1-phenylethyl or 2-phenylethyl,
wherein (C) 1 -C 6 ) The alkyl group may be up to trisubstituted by fluorine,
and is also provided with
Wherein phenyl and phenyl in benzyl, 1-phenylethyl and 2-phenylethyl may be up to trisubstituted by identical or different radicals from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl) thio,
or (b)
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a tetrahydroquinoline ring of formula (c) or a tetrahydroisoquinoline ring of formula (d),
Figure BDA0004107514540000101
wherein the bond to the carbonyl group is marked.
The present invention relates to a combination of a compound of formula (I) and a compound of formula (II), and salts, solvates and solvates of salts thereof
Figure BDA0004107514540000102
Wherein the method comprises the steps of
X represents S, N or O;
y represents N, S or O, and the total number of the catalyst is,
wherein the method comprises the steps of
If X represents S, Y represents N;
z represents a group of compounds C, O, N,
wherein the method comprises the steps of
If X represents N and Y represents N, Z represents O;
R 1 represents a 5-or 6-membered heteroaryl or phenyl group,
wherein the 5-or 6-membered heteroaryl group may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -substituent substitution of alkoxy and halogen;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) The alkoxy groups may in turn be up to trisubstituted by halogen,
wherein the phenyl groups may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 3 -C 5 ) Cycloalkyl, (C) 1 -C 4 ) -substitution of substituents for alkoxy, cyano, hydroxy and halogen;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 2 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
or (b)
And R is R 2 The carbon atoms to which they are attached together form (C 3 -C 4 ) A cycloalkyl ring, which is a ring-shaped member,
R 3 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 4 and is absent when Z represents N or O;
when Z represents C, it represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) -cycloalkyl, phenyl or Halogen;
wherein (C) 1 -C 4 ) Alkyl may in turn be up to trisubstituted by halogen and phenyl may in turn be substituted by halogen,
R 5 represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -an alkoxy group or a halogen group,
R 6 a group of formula a), b), c), d), e), f) or g)
Figure BDA0004107514540000111
Wherein the bond to the adjacent piperidine ring is marked,
wherein R7 represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) -a cyclic alkoxy group or a phenyl group,
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) A cycloalkoxy group and may be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl may in turn be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and may be up to two times by halogen,
wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl groups in turn may be mono-or di-substituted by halogen,
wherein (C) 3 -C 4 ) The cycloalkoxy groups may in turn be up to disubstituted by halogen,
wherein R is 8 Represents hydrogen or fluorine, and is preferably selected from the group consisting of,
wherein R is 9 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -alkoxy or halogen;
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 1 -C 4 ) -an alkoxy group substituted by at least one amino group,
n represents 0 or 1, and the number of the n is,
m represents 0, 1 or 2,
p represents 0, 1 or 2
q represents 0, 1 or 2,
Figure BDA0004107514540000121
wherein the method comprises the steps of
Ring Q represents a piperazine or diazabicyclo system of the formula
Figure BDA0004107514540000131
Meaning and adjacent CHR ’2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 1 、W 2 or W 3 Represents a group of compounds represented by CH or N,
R’ 1 represents halogen, cyano, (C) 1 -C 4 ) -alkyl, cyclopropyl or cyclobutyl
Wherein (C) 1 -C 4 ) Alkyl groups can be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl groups can be up to disubstituted by fluorine,
and is also provided with
R’ 2 Representative (C) 4 -C 6 ) Cycloalkyl wherein ring CH 2 The group may be replaced by an-O-group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or (c) or pyrrolyl of the formula (d), (e), (f) or (g),
Figure BDA0004107514540000141
wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine, chlorine, bromine or methyl,
R’ 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
wherein (C) 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents hydrogen, (C) 1 -C 3 ) -alkoxy, cyclobutoxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono- (C) 1 -C 3 ) -alkylamino, di- (C) 1 -C 3 ) -alkylamino or (C) 1 -C 3 ) -an alkylthio group, which is a group,
wherein (C) 1 -C 3 ) The alkoxy group may be up to trisubstituted by fluorine,
R 7 Represents hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl, cyclopropyl or (C) 1 -C 3 ) -alkoxy groups
Wherein (C) 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R 9 represents hydrogen, (C) 1 -C 3 ) -alkyl or amino
And is also provided with
Wherein in the sub-formula (d)
Y represents O, S or N (CH) 3 )，
Wherein in the sub-formulae (e) and (f)
Y represents O or S, and the like,
or (b)
R’ 2 represents-OR 10 or-NR 11 R 12 A group in which
R 10 Representative (C) 1 -C 6 ) -alkyl, (C) 4 -C 6 ) Cycloalkyl or [ (C) 3 -C 6 ) Cycloalkyl radicals]A methyl group,
R 11 represents hydrogen or (C) 1 -C 3 ) -alkyl group
And is also provided with
R 12 Representative (C) 1 -C 6 ) -alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl or benzyl, 1-phenylethyl or 2-phenylethyl,
wherein (C) 1 -C 6 ) The alkyl group may be up to trisubstituted by fluorine,
and is also provided with
Wherein phenyl and phenyl in benzyl, 1-phenylethyl and 2-phenylethyl may be up to trisubstituted by identical or different radicals from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl) thio,
or (b)
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a tetrahydroquinoline ring of formula (c) or a tetrahydroisoquinoline ring of formula (d),
Figure BDA0004107514540000151
Wherein the bond to the carbonyl group is marked.
In one possible subset of compounds of formula I,
x represents S, and the X represents S,
y represents N, and the number of the N-type fluorescent lamp,
and
Z represents a group of C, wherein Z represents C,
wherein in the resulting groups of formula (h),
Figure BDA0004107514540000152
wherein each represents a bond to a carbonyl group and each represents a bond to an N atom of an adjacent piperidine ring,
R 4 represents hydrogen or chlorine, and the hydrogen is represented by,
in another possible subset of compounds of formula I,
R 1 represents a pyridyl group or a phenyl group,
wherein the pyridyl group may be substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl and trifluoromethoxy;
wherein phenyl may be substituted with 1 or 2 substituents independently selected from methyl, cyclopropyl, methoxy, cyano, hydroxy, fluoro, chloro and trifluoromethyl;
in another possible subset of compounds of formula I,
R 1 represents 3, 5-difluoropyridin-2-yl.
In another possible subset of compounds of formula I,
R 2 represents hydrogen;
or (b)
And R is R 2 The attached carbon atoms together form a cyclopropyl ring.
In another possible subset of compounds of formula I,
R 6 represents a group of formula a),
Figure BDA0004107514540000161
wherein each represents a bond to an adjacent piperidine ring,
and is also provided with
R 7 Represents hydrogen and is used as a hydrogen source,
R‘ 7 methyl, ethyl, n-propyl, isopropyl, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 3-difluorocyclobutylmethoxy A group, 2-trifluoroethoxymethyl, cyclopropylmethyl, 1-fluoromethylcyclopropylmethoxymethyl, 1-difluoromethylcyclopropylmethoxymethyl, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, 3-difluorocyclobutylmethoxymethyl, 3-fluorobutoxymethyl, 2-difluorocyclopropylmethoxy, cyclobutoxy, 3-difluorocyclobutoxy, 2-fluoroethyl, cyclopropyl, cyclobutyl, 2-methoxyethyl or tert-butyl,
or (b)
R 7 And R'. 7 Are linked to each other and together with the carbon atoms to which they are attached form a cyclopropyl ring.
In another possible subset of compounds of formula I,
R 6 represents a group of formula a),
Figure BDA0004107514540000171
wherein each represents a bond to an adjacent piperidine ring,
and is also provided with
R 7 Represents hydrogen and is used as a hydrogen source,
R‘ 7 a methyl group,
or (b)
R 7 And R'. 7 Are linked to each other and form together with the carbon atom to which they are attached a cyclopropyl ring.
In another possible subset of compounds of formula I, n is 1.
In another possible subset of compounds of formula I, m is 1.
In yet another possible subset of compounds of formula I, p is 1.
In yet another possible subset of compounds of formula I, q is 2.
In a further possible subset of the compounds of the formula I, the compounds are N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazol-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide or N- [1- (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-bipiperidin-5-carboxamide, 3-thiazole-5-carboxamide.
A preferred compound of formula (I) is N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide.
In one possible subset of compounds of formula II,
ring Q represents a diazabicyclo system of the formula
Figure BDA0004107514540000181
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached and represents the bond to the carbonyl group,
in one possible subset of compounds of formula II,
ring Q represents a diazabicyclo system of the formula
Figure BDA0004107514540000182
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached represents the bond to the carbonyl group. In another possible subset of the compounds of formula II
W 1 Represents CH.
In another possible subset of the compounds of formula II
W 2 Represents CH.
In another possible subset of the compounds of formula II
W 3 Representing N.
In yet another possible subset of compounds of formula II
R’ 1 Represents chlorine, bromine, isopropyl or cyclopropyl,
in yet another possible subset of compounds of formula II
R’ 2 Phenyl which represents (a)
Figure BDA0004107514540000183
Wherein the bond to the adjacent carbonyl group is marked,
R 4 represents hydrogen, fluorine or chlorine
And is also provided with
R 5 Represents fluorine, chlorine, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
R’ 2 representing a pyridinyl group of formula (b)
Figure BDA0004107514540000191
Wherein the bond linking adjacent carbonyl groups is marked
R' 5 Represents hydrogen, fluorine or chlorine,
R 6 represents methoxy, difluoromethoxy or trifluoromethoxy, in a further possible subset of the compounds of the formula II which are (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazole- [1,2-a ] ]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) methanone or (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) methanone.
In yet another possible subset of compounds of formula II, the compound is (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone or (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone.
A preferred compound of formula (II) is 4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone.
One preferred compound of formula (II) is (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone.
Yet another embodiment of the invention relates to a combination of a compound of formula (I) and a compound of formula (II), salts, solvates and solvates of salts thereof,
in the case of the compounds of the formula (I),
x, Y and Z are selected from S, N, O and C to form a group of (h), (I), (j), (k) or (r)
Figure BDA0004107514540000201
R 1 Represents pyridyl, pyrazolyl, thiazolyl, thienyl or phenyl,
wherein the pyridyl group may be independently selected from 1 or 2 (C) 1 -C 2 ) -alkyl, fluoro, chloro, trifluoromethyl and trifluoromethoxy;
wherein pyrazolyl groups may be selected from 1 or 2 independently (C) 1 -C 2 ) -alkyl, fluoro, chloro, trifluoromethyl and trifluoromethoxy;
wherein the thiazolyl group may be substituted with chlorine,
wherein the thienyl group may be substituted with fluorine,
wherein the phenyl groups may be independently selected from 1 or 2 (C) 1 -C 2 ) -alkyl, (C) 3 -C 4 ) -cycloalkyl, methoxy, cyano, hydroxy, fluoro, chloro and trifluoromethyl substituents;
R 2 represents hydrogen or methyl;
and R is R 2 The attached carbon atoms together form a cyclopropyl ring,
R 3 represents hydrogen or (C) 1 -C 2 ) -an alkyl group;
R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromo, chloro or phenyl;
wherein the phenyl group is replaced with chlorine,
R 5 represents hydrogen or fluorine, and is preferably selected from the group consisting of,
R 6 a group of formula a), b '), c') or e),
Figure BDA0004107514540000202
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represent hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 2 ) -alkoxy, (C) 3 -C 4 ) -cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or phenyl,
Wherein (C) 1 -C 4 ) Alkyl may in turn be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and may be up to disubstituted by fluorine,
wherein the methoxy group may in turn be substituted by cyclopropyl, cyclobutyl or trifluoroethyl,
wherein the cyclopropyl group may in turn be substituted by a monofluoromethyl, difluoromethyl or trifluoromethyl group,
wherein the cyclobutyl group may in turn be substituted by a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group,
wherein (C) 1 -C 2 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl groups in turn may be monosubstituted or disubstituted by fluorine,
wherein (C) 3 -C 4 ) The cycloalkoxy groups may in turn be up to disubstituted by fluorine,
wherein R is 9 Represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluoro or chloro;
n represents 0 or 1, and the number of the n is,
m represents 1 or 2, and the number of m is,
in the compounds of formula (II)
Ring Q represents a piperazine or diazabicyclo system of the formula
Figure BDA0004107514540000211
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 2 represents a group of compounds which are represented by CH,
W 1 、W 3 represents a group of compounds represented by CH or N,
R’ 1 represents fluorine, chlorine, bromine, methyl, tert-butyl, isopropyl, cyclopropyl or cyclobutyl, and
R’ 2 represents a cyclobutyl, a cyclopentyl or a cyclohexyl group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d) or (g)
Figure BDA0004107514540000221
Wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine or chlorine,
R’ 4 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutoxy or methylthio,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
R 9 Represents methyl or amino groups
Y represents O or S or N (CH) 3 )。
Yet another embodiment of the invention relates to a combination of a compound of formula (I) and a compound of formula (II), salts, solvates and solvates of salts thereof,
in the compounds of formula (I)
X, Y and Z are selected from S, N, O or C to form 1, 3-thiazolyl, 1, 3-oxazolyl, or 1,2, 4-oxadiazolyl;
R 1 represents pyridyl, 2-ethylpyridyl, 4, 6-dimethylpyridyl, 3, 5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethylpyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 3-chlorophenyl, 1-chloro-1, 5-thienyl, 1-chloro-1-thiazolyl;
R 2 Represents hydrogen or methyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, methyl, ethyl or trifluoromethyl;
wherein the phenyl group may in turn be substituted by chlorine,
R 5 represents hydrogen or fluorine, and is preferably selected from the group consisting of,
R 6 a group representing formula a), c') or c "),
Figure BDA0004107514540000231
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutyl-methoxymethyl 2, 2-trifluoroethoxy, 2-trifluoroethoxymethyl, 2-difluorocyclopropyl-methoxy cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy or fluorine;
n represents 0 or 1, and the number of the n is,
m represents a group of 1,
in the case of the compounds of the formula (II),
ring Q represents a piperazine or diazabicyclo system of the formula
Figure BDA0004107514540000241
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 2 represents a group of compounds which are represented by CH,
W 1 ，W 3 represents a group of compounds represented by CH or N,
R’ 1 represents fluorine, chlorine, bromine, methyl, tert-butyl, isopropyl, cyclopropyl or cyclobutyl, and
R’ 2 represents a cyclobutyl, a cyclopentyl or a cyclohexyl group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d) or (g)
Figure BDA0004107514540000242
Wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine or chlorine,
R’ 4 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutoxy or methylthio,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
R 9 Represents a methyl group or an amino group,
y represents O or S or N (CH) 3 )。
Still another embodiment of the present invention relates to a combination of a compound of formula (I) and a compound of formula (II), and salts, solvates and solvates of salts thereof,
in the case of the compounds of the formula (I),
x, Y and Z are selected from S, N, O and C to form a 1, 3-thiazolyl, 1, 3-oxazolyl or 1,2, 4-oxadiazolyl group,
R 1 represents pyridyl, 2-ethylpyridyl, 4, 6-dimethylpyridyl, 3, 5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethylpyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1, 3-thiazolyl, 5-fluoro-2-thienyl;
R 2 represents hydrogen or methyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, methyl, ethyl or trifluoromethyl;
wherein the phenyl group may in turn be substituted by chlorine,
R 5 represents hydrogen or fluorine;
R 6 a group representing formula a), c') or c "),
Figure BDA0004107514540000261
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutyl-methoxymethyl 2, 2-trifluoroethoxy, 2-trifluoroethoxymethyl, 2-difluorocyclopropyl-methoxy cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy or fluorine;
n represents 0 or 1, and the number of the n is,
m represents a group of 1,
in the compounds of formula (II)
Ring Q represents a diazabicyclo system of the formula
Figure BDA0004107514540000262
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 1 represents a group of compounds which are represented by CH,
W 2 represents a group of compounds which are represented by CH,
W 3 represents a group of compounds represented by the formula N,
R’ 1 represents fluorine, chlorine, bromine, methyl, isopropyl, cyclopropyl or cyclobutyl,
R’ 2 represents cyclobutyl, cyclopentyl or cyclohexyl
Or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d), (e) or (f)
Figure BDA0004107514540000271
Wherein the bond linking adjacent carbonyl groups is marked
R 4 Represents hydrogen, fluorine or chlorine,
R 5 represents fluorine, chlorine, cyano, (C) 1 -C 3 ) -alkyl, (C) 1 -C 3 ) An alkoxy group or a trifluoromethoxy group,
R δ represents hydrogen, fluorine, chlorine, bromine or methyl,
R 7 representative (C) 1 -C 3 ) -alkoxy, cyclobutoxy or (C) 1 -C 3 ) -an alkylthio group, which is a group,
wherein (C) 1 -C 3 ) The alkoxy group may be up to trisubstituted by fluorine,
R 9A and R is 9B Identical or different and independently of one another represent hydrogen, chlorine, bromine, (C) 1 -C 3 ) -an alkyl group or a cyclopropyl group,
wherein (C) 1 -C 3 ) The alkyl group may be up to trisubstituted by fluorine,
and is also provided with
Y represents o or S.
Still another embodiment of the present invention relates to a combination of a compound of formula (I) and a compound of formula (II), salts, solvates and solvates of salts thereof,
in the case of the compounds of the formula (I),
x, Y and Z are selected from S, N, O and C to form 1, 3-thiazolyl, 1, 3-oxazolyl or 1,2, 4-oxadiazolyl;
R 1 Represents pyridyl, 2-ethylpyridyl, 4, 6-dimethylpyridyl, 3, 5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethylpyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 3-chlorophenyl, 1-chloro-1, 5-thienyl, 1-chloro-1-thiazolyl;
R 2 represents hydrogen or methyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, methyl, ethyl or trifluoromethyl;
wherein the phenyl group may in turn be substituted by chlorine,
R 5 represents hydrogen or fluorine, and is preferably selected from the group consisting of,
R 6 a group representing formula a), c') or c "),
Figure BDA0004107514540000281
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cycloPropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl 3, 3-difluorocyclobutyl-methoxymethyl, 2-trifluoroethoxy, 2-trifluoroethoxymethyl, 2-difluorocyclopropyl-methoxy, cyclobutoxy 3, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy or fluorine;
n represents 0 or 1, and the number of the n is,
m represents a group of 1,
in the case of the compounds of the formula (II),
ring Q represents a diazabicyclo system of the formula
Figure BDA0004107514540000282
Wherein is represented by and adjacent CHR 2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 1 represents a group of compounds which are represented by CH,
W 2 represents a group of compounds which are represented by CH,
W 3 represents a group of compounds represented by the formula N,
R’ 1 represents chlorine, bromine, isopropyl or cyclobutyl,
and is also provided with
R’ 2 Represents a cyclopentyl group or a cyclohexyl group, and is preferably a cyclohexyl group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d), (e) or (f)
Figure BDA0004107514540000291
Wherein the bond linking adjacent carbonyl groups is marked
R 4 Represents hydrogen, fluorine or chlorine,
R 5 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R 6 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 7 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutoxy or methylthio,
R 9A and R is 9B Identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and is also provided with
Y represents O or S.
In a preferred embodiment of the invention, the following combinations are involved: n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclopropylmethyl) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (difluoromethyl) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazolo-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (trifluoromethyl) [1,4' -bipiperidin-2-yl ] -1, 3-thiazole-5-carboxamide as compounds of formula (I), N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (fluoromethyl) - [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-methyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoro-pyridin-2-yl) methyl ] -4-methyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl ] -1, 4' -bipiperidin-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -4- (trifluoromethyl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -5-ethyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -5-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methoxy [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [3- (difluoromethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-ethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- { [4- (trifluoromethyl) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [3- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-2-yl) methyl ] -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [4- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide, N- [ (5-chloro-3-fluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (3-methylpyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (4-methylpyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-chloropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-2-yl) methyl ] -N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- { [6- (trifluoromethyl) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, N- [ (5-chloropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3-chloro-5-fluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -N- { [6- (trifluoromethoxy) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, N- (4-chlorobenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-chloro-5-fluorobenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (4-methylbenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-methylbenzyl) -2- [ (3R) -3-methyl- [1,4' -bipiperidin ] -1' -yl ] -1, 4' -bipiperidin ] -1-yl, 3-thiazole-5-carboxamide, N- (2-methylbenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3S) - (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- { (3S) -3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- { (3R) -3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (1S) -1- (2, 5-difluorophenyl) ethyl ] -3- [ (1R) -3-methyl-, 4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (1R) -1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -3- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1,2, 4-oxadiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -3- [ (3R), (3 'R) -3' -fluoro-3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R), (3 'S) -3' -fluoro-3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, N- [1- (3, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [1- (3, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3-methyl ] -1, 3-thiazol-5-carboxamide, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (5-fluoro-2-thienyl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -N- (pyridin-4-ylmethyl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {3- [ (2, 2-trifluoroethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) [1,4' -bipiperidin ] -1, 3-thiazole-5-carboxamide, 2- [3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3, 3-dimethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazol-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazol-5-carboxamide, 2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-1-yl) methyl ] -2- [ (3, 3-difluoro-5-methyl ] -1-thiazol-5-carboxamide, 3-thiazole-5-carboxamide, 2- [3- (cyclobutylmethoxy) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclopropylmethoxy) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclobutoxy) methyl ] - [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclopropylmethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ 3-ethoxy [1,4' -bipiperidin ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {4- [ (3R) -3-methylpiperidin-1-yl ] azepan-1-yl } -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [ (6-methylpyridin-3-yl) methyl ] -1, 3-thiazole-5-carboxamide, N-benzyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [ 3-fluorobutyl ] oxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- (3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } [1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-4-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2, 2-trifluoroethoxy) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (4, 6-dimethylpyridin-3-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (4-chloro-1-methyl-IH-pyrazol-5-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-methoxybenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-carboxamide, 5-difluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-hydroxybenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (2R) -2-phenylpropyl ] -1, 3-thiazole-5-carboxamide, N- (4-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-3-ylmethyl) -1, 3-thiazole-5-carboxamide, N- (3-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-chloro-4-fluorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-cyano-4-fluorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-3-ylmethyl) -1, 3-thiazole-5-carboxamide, N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-4-ylmethyl) -1, 3-thiazole-5-carboxamide, N-benzyl-N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl, 3-thiazole-5-carboxamide, N- (2-cyclopropylphenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-chlorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [ (1R) -1- (4-methylphenyl) ethyl ] -1, 3-thiazole-5-carboxamide, N- (2-ethylpyridin-4-yl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- { (3S) -3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- { (3R) -3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-isopropyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- ((4S) -4-methylazepan-1-yl) piperidin-1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- ((4R) -4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- { (3S) -3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- { (3R) -3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, 2- {3- [ (2, 2-difluorocyclopropyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclobutoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (1, 4 '-bipiperidin ] -3' -yl), 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (3, 3-difluorocyclobutyl) oxy ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- [ (cyclopropyl) methoxy ], 4' -bipiperidin-1 ' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclopropylmethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4- (2-chlorophenyl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-bromo-3-carboxamide, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-propyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 4-cyclopropyl-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- ((3S) -3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, N- [ (3R) -3-thiazole-5-carboxamide, 5-difluoropyridin-2-yl) methyl ] -2- ((3R) -3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 2- [ (3S) -3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, formic acid-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2-fluoroethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- ([ 1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [3- (3-fluoroethyl) methyl ], 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-ethyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (3S) - (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [4- (3R) - (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) piperidin-1-yl ] -N- [ (3, 5-difluoro-methyl ] -1, 4' -bipiperidin-1-yl), 3-thiazole-5-carboxamide, 2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
And a compound of formula (II) selected from:
(4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-fluorophenyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (3-methoxyphenyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-chloro-5-fluorophenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-fluorophenyl) methanone, (4- { [2- (4-fluorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclohexyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclohexyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (tetrahydrofuran-3-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclobutyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-methoxyphenyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (5-fluoro-2-methoxyphenyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-methylphenyl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (5-fluoro-2-methylphenyl) methanone, (2-chloro-5-fluorophenyl) (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclohexyl) methanone, ((4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclobutyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (3-methoxyphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-methoxyphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (5-fluoro-2-methoxyphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-methylphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (5-fluoro-2-methylphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [3- (trifluoromethoxy) phenyl]Methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [3- (trifluoromethyl) phenyl]Methanone, ((4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (pyridin-2-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-fluoro-5-methoxyphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-ethoxyphenyl) methanone, (2-chloro-5-methoxyphenyl) (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (tetrahydro-2H-pyran-2-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (3-isopropoxyphenyl) methanone, 2- [ (4- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl ]Methyl } piperazin-1-yl) carbonyl]Benzonitrile, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (3-isopropylphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-isopropylphenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (tetrahydrofuran-2-yl) methanone, (3-chlorophenyl) (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (2-chlorophenyl) (4- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [6- (2, 2-trifluoroethoxy) pyridin-2-yl]Methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-isopropoxypyridin-2-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxy-4-methylpyridin-2-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [6- (cyclobutoxy) pyridin-2-yl]Methanone, (3-bromo-6-methoxypyridin-2-yl) (4- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [6- (difluoromethoxy) pyridin-2-yl]Methanone, (4- { [2- (4-chlorophenyl) mi-rideAzolo [1,2-a ]]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-ethoxypyridin-2-yl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [6- (tetrahydro-2H-pyran-4-yloxy) pyridin-2-yl]Methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (4- { [2- (4-fluorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-fluorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclobutyl) methanone, (5-fluoro-2-methoxyphenyl) (4- { [2- (4-fluorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (2-chloro-5-fluorophenyl) (4- { [2- (4-fluorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-fluorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-methoxyphenyl) methanone, (2-fluorophenyl) (4- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, cyclopentyl (4- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, cyclopentyl (4- { [2- (4-methylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, cyclohexyl (4- { [2- (4-methylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (2-methoxyphenyl) (4- { [2- (4-methylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (6-methoxypyridin-2-yl) (4- { [2- (4-methylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) methanone, (4- (3- { [4- (2-fluorobenzoyl) piperazin-1-yl)]Methyl } imidazo [1,2-a]Pyridin-2-yl) benzonitrile and 4- [3- ({ 4- [ (6-methoxypyridin-2-yl) carbonyl }]Piperazin-1-yl } methyl) imidazo [1,2-a]Pyridin-2-yl]Benzonitrile, 4- (3- { [4- (cyclopentylcarbonyl) piperazin-1-yl]Methyl } imidazo [1,2-a]Pyridin-2-yl) benzonitrile, 4- (3- { [4- (cyclohexylcarbonyl) piperazin-1-yl ]Methyl } imidazo [1,2-a]Pyridin-2-yl) benzonitrile, (4- { [2- (4-tert-butylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (4- { [2- (4-tert-butylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-Fluorophenyl) methanone, (4- { [2- (4-tert-butylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) [6- (trifluoromethoxy) pyridin-2-yl]Methanone, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (4- { [2- (4-cyclopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (2-fluorophenyl) methanone, 4- (3- { [4- (2-fluoro-5-methoxybenzoyl) piperazin-l-yl]Methyl } imidazo [1-2-a]Pyridin-2-yl) benzonitrile and 4- [3- ({ 4- [ (6-methoxy-3-methylpyridin-2-yl) carbonyl)]Piperazin-l-yl } methyl) imidazo [1,2-a]Pyridin-2-yl) benzonitrile, (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3 yl]
Figure BDA0004107514540000371
Methyl } piperazin-1-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (4- { [2- (4-tert-butylphenyl) imidazo [1, 2-a) ]-pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]
Figure BDA0004107514540000372
Methyl } piperazin-1-yl) (6-methoxy-3-methyl-pyridin-2-yl) methanone; tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, tert-butyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](6-methoxypyridin-2-yl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](cyclopentyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-fluorophenyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydroPyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-chloro-5-fluorophenyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](cyclohexyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](cyclobutyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3-methoxyphenyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-methoxyphenyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](5-fluoro-2-methoxyphenyl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-methylphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-fluorophenyl) methanone, (2-chloro-5-fluorophenyl) [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl]Methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c ]Pyrrol-2 (1H) -yl](cyclohexyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3-methoxyphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-methoxyphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](5-fluoro-2-methoxyphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](2-methylphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](5-fluoro-2-methylphenyl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl][3- (trifluoromethoxy) phenyl ]]Methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H)) -base group][3- (trifluoromethyl) phenyl ]]Methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c ]Pyrrol-2 (1H) -yl](6-methoxypyridin-2-yl) methanone, [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](6-methoxypyridin-2-yl) methanone, (2-fluorophenyl) [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl]Methanone, [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3-methoxyphenyl) methanone, cyclopentyl [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl]Methanone, 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-methyl-N-phenylhexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamides, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3, 4-dihydro-quinolin-1 (2H) -yl) methanone, [5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3, 4-Dihydroisoquinolin-2 (1H) -yl) methanone, isobutyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl ]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, benzyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, cyclopentyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, isopropyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, 3- (trifluoromethyl) phenyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, fluoroethyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid ester, 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 4-difluorophenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 6-difluorobenzyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acidAmine, 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 6-dimethylphenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -N- (2-fluorophenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2-ethoxyphenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (4-chloro-3- (trifluoromethyl) phenyl)]Hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- [ 2-chloro-5- (trifluoromethyl) phenyl group]Hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (cyclohexyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide, rac-5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (1-phenylethyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (4-fluorophenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxamide, (3-fluoro-6-methoxypyridin-2-yl) [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl]Methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](6-methoxy-3-methylpyridin-2-yl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl](3-fluoro-6-methoxypyridin-2-yl) methanone, 3-chloro-6-methoxypyridin-2-yl) [5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl]Methanone, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylate, tert-butyl 8- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo[3.2.1]Octane-3-carboxylic acid ester, tert-butyl 8- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-3-carboxylate, tert-butyl 8- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl ]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-3-carboxylic acid ester, tert-butyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid ester, tert-butyl 3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid ester, tert-butyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 3- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl](6-methoxypyridin-2-yl) methanone, (-) - (3-chloro-6-methoxypyridin-2-yl) [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl]Methanone, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, (5- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone(3-chloro-6-methoxypyridin-2-yl) (5- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (-) - (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (6-methoxypyridin-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [6- (cyclobutoxy) pyridin-2-yl]Methanone, (3-chloro-6-methoxypyridin-2-yl) (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, (3- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (+) - - [ (1R, 4R) -5- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2 ]Oct-2-yl](6-methoxypyridin-2-yl) methanone, (-) - (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (+) - (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, 5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (cyclopentyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (cyclopentyl) methanone, (-) - (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (+) - (5- { [2- (4-)Chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (2-chloro-5-fluorophenyl) (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (cyclohexyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (cyclobutyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (5-fluoro-2-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-methylphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (5-fluoro-2-methylphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) [3- (trifluoromethoxy) phenyl]Methanone, (3-chlorophenyl) (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) [3- (trifluoromethyl) phenyl ]]Methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2 ]Oct-2-yl) (pyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (1-methyl-1H-imidazol-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methylphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-ethoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (pyridin-4-yl) methanone, (-) - (2-fluorophenyl) (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridine compound-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (+) - (2-fluorophenyl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (-) - (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (+) - (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (-) - (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (+) - (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, cyclopentyl (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, cyclopentyl (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (-) - (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (+) - (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (2-fluorophenyl) (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (2-fluorophenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (3-methoxyphenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (cyclopentyl) methanones(7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [3- (trifluoromethoxy) phenyl ]]Methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (2-isopropylphenyl) methanone, (2-chloro-5-methoxyphenyl) (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (5-fluoro-2-methoxyphenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (3-isopropylphenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [6- (2, 2-trifluoroethoxy) pyridin-2-yl]Methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (tetrahydrofuran-3-yl) methanone, (3-chlorophenyl) (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [6- (trifluoromethoxy) pyridin-2-yl]Methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (8- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (2-fluorophenyl) methanone, (8- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (6-methoxypyridin-2-yl) methanone, (8- { [2- (4-bromophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (3-methoxyphenyl) methanone, (8- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (cyclopentyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (cyclopentyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl }-3, 8-diazabicyclo [3.2.1]Oct-3-yl) (2-fluorophenyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (5-fluoro-2-methylphenyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (5-fluoro-2-methoxyphenyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (2-methylphenyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (2-methoxyphenyl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1 ]Oct-3-yl) (6-methoxypyridin-2-yl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (cyclohexyl) methanone, (2-fluorophenyl) (8- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) methanone, (8- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclopentyl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-methoxyphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-methylphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclobutyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-fluoro-2-methoxyphenyl)) Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclohexyl) methanone, (2-chloro-5-fluorophenyl) (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-fluoro-2-methylphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-methoxyphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1 ]Oct-8-yl) (2-methoxyphenyl) methanone, (2-fluorophenyl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) methanone, (3- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-methoxyphenyl) methanone, (3- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclopentyl) methanone, (3-chlorophenyl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (tetrahydrofuran-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (cyclopentyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (2-fluorophenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (cyclohexyl) methanone, (2-chloro-5-fluorophenyl) (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -36-diazabicyclo [3.1.1]Hept-6-yl) [3- (trifluoromethoxy) phenyl ]]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (cyclobutyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (3-ethoxyphenyl) methanone, cyclopentyl (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) methanone, (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (2-fluorophenyl) (5- { [2- (6-isopropylpyridin-3-yl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octan-2-yl) methanone, t-butyl 7- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylate, tert-butyl 3- { [2- (6-isopropylpyridin-3-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (6-isopropylpyridin-3-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylic acid ester, (7- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [6- (trifluoromethoxy) pyridin-2-yl]Methanones, (3-chloro-6-methoxypyridin-2-yl) (7- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl](6-methoxy-3-methylpyridin-2-yl) methanone, 5- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl](6-methoxy-3-methylpyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-chloro-6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-isopropylphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.1.1]Hept-6-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (8- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (8- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-3-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (4-isopropyl-1, 3-thiazol-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (1, 3-thiazol-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (4-methyl-1, 3-thiazol-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-methyl-1, 3-thiazol-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (4, 5-dimethyl-1, 3-thiazol-2-yl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone and 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -N-isopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide,3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2-fluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 6-dichlorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 6-dimethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-pentyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2-methylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- [ 2-chloro-5- (trifluoromethyl) phenyl group]-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (4-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2-ethyl-6-methylphenyl) -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 5-dimethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-cyclohexyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (2-chloro-6-methylphenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 6-difluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N- (2, 4-dimethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-isopropyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, N- (2-chloro-6-methylphenyl) -7- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-cyclopropyl-3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxamideAmine, N- (2-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-methyl-N-phenyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (morpholin-4-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -N, N-diisopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-cyclohexyl-N-ethyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (pyrrolidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -N-ethyl-N-phenyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-isopropyl-N-methyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (piperidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -N, N-dimethyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-ethyl-N- (4-methylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (4-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-isopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (thiomorpholin-4-yl) methanone, methyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, ethyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, cyclopentyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, cyclohexyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl group3, 8-diazabicyclo [3.2.1 ] ]Octane-8-carboxylic acid ester, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N, N-diethyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (morpholin-4-yl) methanone, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N, N-diisopropyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-cyclohexyl-N-ethyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (pyrrolidin-1-yl) methanone, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-ethyl-N-phenyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -N-isopropyl-N-methyl-3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxamide, ethyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1 ]Nonane-9-carboxylate, cyclopentyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylate, propyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylic acid ester, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (piperidin-1-yl) methanones, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyridin-3-yl]-methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-chloro-6-methoxypyridin-2-yl) methanone, (5- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) [6- (difluoromethoxy) pyridin-2-yl]Methanone, tert-butyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylate, tert-butyl 7- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Nonane-9-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 3- {1- [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Ethyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, tert-butyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylate, tert-butyl 3- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid ester, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1 ]Non-9-yl) methanones, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) [6- (methylthio) pyridin-2-yl]Methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (cyclopentyl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (7- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, [6- (difluoromethoxy) pyridin-2-yl](7- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl)) Imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5-cyclopropyl-1, 3-oxazol-4-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl ]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (2-fluorophenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (3-methoxyphenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [6- (methylthio) pyridin-2-yl]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclopentyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [6- (methylamino) pyridin-2-yl]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazaBicyclo [3.2.1]Oct-8-yl) (3-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2 ]Oct-2-yl) (cyclopentyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2 ]Oct-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (5-cyclopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-cyclopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-methyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-isopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2, 4-dimethyl-1, 3-oxazol-5-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-ethyl-1, 3-oxazol-4-yl) methanone, (4-bromo-5-methyl-1, 3-thia-tionOxazol-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-cyclopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2-isopropyl-1, 3-thiazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (1, 3-thiazol-5-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (2, 5-dimethyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [ 2-methoxy-4- (trifluoromethyl) -1, 3-thiazol-5-yl]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [2- (trifluoromethyl) -1, 3-thiazol-4-yl]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (5-methyl-1, 3-thiazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1 ]Oct-8-yl) [4- (trifluoromethyl) -1, 3-thiazol-2-yl]Methanone, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (1, 3-thiazol-4-yl) methanone, (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [6- (methylamino) pyridin-2-yl]Methanone, (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (2-fluorophenyl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, (3- {1- [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Ethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (7- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) (6-methoxypyridin-2-yl) methanone,(3-chloro-6-methoxypyridin-2-yl) (7- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanones, (2-fluorophenyl) (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -3-oxo-7, 9-diazabicyclo [3.3.1]Non-9-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5-cyclopropyl-1, 3-oxazol-4-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) methanone, (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxypyridin-2-yl) methanone, [6- (difluoromethoxy) pyridin-2-yl ]](5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2 ]Oct-2-yl) methanone, (5- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (cyclopentyl) methanone, (5- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -2, 5-diazabicyclo [2.2.2]Oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) (2-fluorophenyl) methanone, (-) -3- { [2- (4-bromophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (cyclopentyl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -N- (2, 4-difluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -N-isopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-cyclopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 5-dichloro-4-methoxyphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (3-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 6-difluorobenzyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 6-dichlorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 6-dimethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2-fluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl ]Methyl } -N- (2, 3-dichlorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2-ethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (2-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- [ 2-chloro-5- (trifluoromethyl) phenyl group]-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2-ethyl-6-methylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 5-dimethylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-cyclohexyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-isobutyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl ]Methyl } -N- (3, 4-dimethoxyphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- {4- [ (trifluoromethyl) thio]Phenyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (3-fluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2, 6-difluorophenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- [ 4-chloro-2- (trifluoromethyl) phenyl group]-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (2-methylbenzyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-methyl-N-phenyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N, N-diethyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (morpholin-4-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -N, N-diisopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-cyclohexyl-N-ethyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (pyrrolidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -N-ethyl-N-phenyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N-isopropyl-N-methyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chloro) 2Phenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (piperidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -N-ethyl-N- (4-methylphenyl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, N- (4-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl ]Methyl } -N-isopropyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N, N-dimethyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (4-ethoxyphenyl) -N-methyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -N- (3-methoxybenzyl) -N-methyl-3, 8-diazabicyclo [3.2.1]Octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (thiomorpholin-4-yl) methanone, methyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, ethyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, cyclopentyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, propyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxylate, cyclohexylmethyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, cyclohexyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylate, 2-dimethylpropyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane 8 formate, t-butyl 3 { [2 (4) isopropylphenyl) imidazo [1,2 a ]]Pyrimidinyl 3]Methyl } -3, 8-diazabicyclo [3.2.1]Octane 8 formate, (5-cyclopropyl 1, 3-oxazol 4-yl) (3- { [2 (4 isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, t-butyl 3- { [2 x (4-cyclopropylphenyl) imidazo [1,2-a ]]Pyrimidine3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octane 8-carboxylate, (3 { [2- (4-cyclopropylphenyl) imidazo [1,2-a ]]Pyrimidine-3-yl]Methyl } -3,8 diazabicyclo [3.2.1 ]]Oct-8-yl) (2-fluorophenyl) methanone, cyclopentyl (3- { [2 x (4 x cyclopropylphenyl) imidazo [1, 2-a)]Pyrimidinyl 3]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8 x yl) methanone, (3 x { 2 x (4 x cyclopropylphenyl) imidazo [1, 2-a) ]Pyrimidine-3-yl]Methyl }. Times.3, 8. Times.diazabicyclo [3.2.1]Oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl }. Times.3, 8. Times.diazabicyclo [3.2.1]Oct-8-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) [6- (difluoromethoxy) pyridin-2-yl]Methanones, (5-cyclopropyl-1, 3-oxazol-4-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone, tert-butyl 6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Nonane-2-carboxylate, tert-butyl 6- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Nonane-2-carboxylate, tert-butyl 6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Nonane-2-carboxylate, (-) -tert-butyl 6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Nonane-2-carboxylate, tert-butyl 9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Nonane-3-carboxylic acid ester, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Decyl-10 radical](3-fluoro-6-methoxypyridin-2-yl) methanone, 3 { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](3-fluoro-6-methoxypyridin-2-yl) methylKetones, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl }. Times.2, 6. Times.diazabicyclo [3.2.2]Non-2 x radical](3-fluoro-6-methoxypyridin-2-yl) methanone, [6- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl }. Times.2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, [6- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridine-3-yl]Methyl }. Times.2, 6. Times.diazabicyclo [3.2.2]Non-2-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl }. Times.2, 6-diazabicyclo [3.2.2]Non-2 x radical](6-methoxypyridin-2-yl) methanone, [6 { [2 ]]Pyrimidine-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](2 x fluorophenyl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanones, (4-amino-1, 2-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](2-fluorophenyl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanones, (4-amino-1, 2, 5-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](2-fluorophenyl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](2-fluorophenyl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidine-3-diopsideBase group]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanones, (4-amino-1, 2, 5-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](2-fluorophenyl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanones, (4-amino-1, 2, 5-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2 ]Non-2-yl]Methanone, cyclopentyl [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- (difluoromethoxy) pyridin-2-yl ]][6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, (2-fluorophenyl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, (2-fluorophenyl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl](6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, [6- (difluoromethoxy) pyridin-2-yl ]][6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, cyclopentyl [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl]Methanone, (3-fluoro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, (3-chloro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl](6-methoxypyridin-2-yl) methanone, [6- (difluoromethoxy) pyridin-2-yl ]][9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, cyclopentyl [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, (3-fluoro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, (3-chloro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] ]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl](6-methoxypyridin-2-yl) methanone, [6- (difluoromethoxy) pyridin-2-yl ]][9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, cyclopentyl [9- { [2- (4-isopropylphenyl) imidazo [1 ]，2-a]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, (-) - (2-fluorophenyl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-3-yl]Methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -2, 6-diazabicyclo [3.2.2]Non-2-yl][6- (trifluoromethoxy) pyridin-2-yl ]]Methanone, [6 { [2 ]]Pyrimidine-3-yl]Methyl }. Times.2, 6-diazabicyclo [3.2.2]Non-2-yl][6- (difluoromethoxy) pyridin-2-yl]Methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](2-fluorophenyl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] ]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](6-methoxypyridin-2-yl) methanone, (3- { [2 x (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl }, 8, 3, 10 diazabicyclo [4.3.1]Decyl 10-yl](2-fluorophenyl) methanone, [3- { [2 ]]Pyridin-3-yl]Methyl }.8-oxo-3, 10 diazabicyclo [4.3.1]Dec-10-yl](6-methoxypyridin-2-yl) methanone, [3 { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](4-methyl-1, 2, 5-oxadiazol-3-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](2-fluorophenyl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](4-methyl-1, 2, 5-oxadiazol-3-yl) methanone, (4-amino-1, 2, 5-oxadiazol-3-yl) [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1 ]Dec-10-yl]Methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](2-fluorophenyl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo[4.2.1]Non-9-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl](2-fluorophenyl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2 x a ]]Pyridin-3-yl]Methyl }. Times.3, 9. Times.diazabicyclo [4.2.1]Non-9-yl](6 x methoxy pyridine x 2 x base) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl }.8-oxo-3, 10 diazabicyclo [4.3.1]Dec-10-yl ](3-fluoro-6-methoxypyridin-2-yl) methanone, [3 { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidinyl 3]Methyl } -8-oxo-3, 10-diazabicyclo [4.3.1]Dec-10-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3 { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridine-3-yl]Methyl } -3, 6-diazabicyclo [3.2.2]Nonx 6-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.2.2]Non-6-yl](6-methoxypyridin-2-yl) methanone, [3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ]]Pyridin-3-yl]Methyl } -3, 6-diazabicyclo [3.2.2]Non-6-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 6-diazabicyclo [3.2.2]Non-6-yl](3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 6-diazabicyclo [3.2.2]Non-6-yl](6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl) methanones, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (5-chloropyridin-2-yl) imidazo [1, 2-a) ]Pyridin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Non-9-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Nonan-9-yl]Methanone, (3-fluoro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Nonan-9-yl]Methanone, [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Nonan-9-yl](6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ]]Pyrimidin-3-yl]Methyl } -3, 9-diazabicyclo [4.2.1]Nonan-9-yl]A ketone.
In a preferred embodiment of the invention, the following combinations are involved: n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclopropylmethyl) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (difluoromethyl) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazolo-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (trifluoromethyl) [1,4' -bipiperidin-2-yl ] -1, 3-thiazole-5-carboxamide as compounds of formula (I), N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (fluoromethyl) - [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-methyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoro-pyridin-2-yl) methyl ] -4-methyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl ] -1, 4' -bipiperidin-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -4- (trifluoromethyl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -5-ethyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -5-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methoxy [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [3- (difluoromethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-ethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- { [4- (trifluoromethyl) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [3- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-2-yl) methyl ] -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [4- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide, N- [ (5-chloro-3-fluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (3-methylpyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (4-methylpyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-chloropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-2-yl) methyl ] -N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- { [6- (trifluoromethyl) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, N- [ (5-chloropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3-chloro-5-fluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -N- { [6- (trifluoromethoxy) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide, N- (4-chlorobenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-chloro-5-fluorobenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (4-methylbenzyl) -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-methylbenzyl) -2- [ (3R) -3-methyl- [1,4' -bipiperidin ] -1' -yl ] -1, 4' -bipiperidin ] -1-yl, 3-thiazole-5-carboxamide, N- (2-methylbenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3S) - (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- { (3S) -3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- { (3R) -3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (1S) -1- (2, 5-difluorophenyl) ethyl ] -3- [ (1R) -3-methyl-, 4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (1R) -1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -3- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1,2, 4-oxadiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -3- [ (3R), (3 'R) -3' -fluoro-3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R), (3 'S) -3' -fluoro-3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, N- [1- (3, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [1- (3, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3-methyl ] -1, 3-thiazol-5-carboxamide, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (5-fluoro-2-thienyl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -N- (pyridin-4-ylmethyl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {3- [ (2, 2-trifluoroethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) [1,4' -bipiperidin ] -1, 3-thiazole-5-carboxamide, 2- [3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazol-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3, 3-dimethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazol-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazol-5-carboxamide, 2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-1-yl) methyl ] -2- [ (3, 3-difluoro-5-methyl ] -1-thiazol-5-carboxamide, 3-thiazole-5-carboxamide, 2- [3- (cyclobutylmethoxy) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclopropylmethoxy) [1,4' -bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclobutoxy) methyl ] - [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclopropylmethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ 3-ethoxy [1,4' -bipiperidin ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {4- [ (3R) -3-methylpiperidin-1-yl ] azepan-1-yl } -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [ (6-methylpyridin-3-yl) methyl ] -1, 3-thiazole-5-carboxamide, N-benzyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [ 3-fluorobutyl ] oxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- (3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } [1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3-fluoropyridin-4-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2, 2-trifluoroethoxy) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (4, 6-dimethylpyridin-3-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (4-chloro-1-methyl-1H-pyrazol-5-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-methoxybenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-thiazole-5-carboxamide, 5-difluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-hydroxybenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [ (2R) -2-phenylpropyl ] -1, 3-thiazole-5-carboxamide, N- (4-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-3-ylmethyl) -1, 3-thiazole-5-carboxamide, N- (3-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (2-chloro-4-fluorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-cyano-4-fluorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-3-ylmethyl) -1, 3-thiazole-5-carboxamide, N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- (pyridin-4-ylmethyl) -1, 3-thiazole-5-carboxamide, N-benzyl-N-methyl-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl, 3-thiazole-5-carboxamide, N- (2-cyclopropylphenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- (3-chlorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [ (1R) -1- (4-methylphenyl) ethyl ] -1, 3-thiazole-5-carboxamide, N- (2-ethylpyridin-4-yl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- { (3S) -3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- { (3R) -3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-isopropyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- ((4S) -4-methylazepan-1-yl) piperidin-1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- ((4R) -4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- { (3S) -3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- { (3R) -3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide, 2- {3- [ (2, 2-difluorocyclopropyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [3- (cyclobutoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (1, 4 '-bipiperidin ] -3' -yl), 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (3, 3-difluorocyclobutyl) oxy ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-4-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-oxazol-4-carboxamide, N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- [ (cyclopropyl) methoxy ], 4' -bipiperidin-1 ' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- {3- [ (cyclopropylmethoxy) methyl ] [1,4' -bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4- (2-chlorophenyl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-bromo-3-carboxamide, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoro-pyridin-2-yl) methyl ] -2- (3-propyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 4-cyclopropyl-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- ((3S) -3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, N- [ (3R) -3-thiazole-5-carboxamide, 5-difluoropyridin-2-yl) methyl ] -2- ((3R) -3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide, 2- [ (3S) -3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [ (3R) -3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, formic acid-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2-fluoroethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- ([ 1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [3- (3-fluoroethyl) methyl ], 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-ethyl-2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (3S) - (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [4- (3R) - (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) piperidin-1-yl ] -N- [ (3, 5-difluoro-methyl ] -1, 4' -bipiperidin-1-yl), 3-thiazole-5-carboxamide, 2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
And a compound of formula (II) selected from:
tert-butyl 7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] nonane-9-carboxylate, tert-butyl 7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] nonane-9-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2 ] octane-2-carboxylate, tert-butyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] nonane-9-carboxylate, tert-butyl 5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] octane-carboxylate, tert-butyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 2-diazabicyclo [2.2.2] 2-carboxylate Tert-butyl 5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate, tert-butyl 3- {1- [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] ethyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, tert-butyl 5- { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate, tert-butyl 3- { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 7-diazabicyclo [ 2.2-2-a ] methyl ] -3-yl) (3, 6-methoxy) (3, 6-chloro-1-chlorophenyl) imidazo [3.2, 2-a ] methyl ] -7-pyrido (3, 6-methoxy) (1, 6-methoxy-1-pyrido), 2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) [6- (methylthio) pyridin-2-yl ] methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) (3-fluoro-cyclopentyl) imidazo [1,2-a ] pyrimidin-3-yl) methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [ 3.1-yl ] non-9-yl ] methanone [6- (difluoromethoxy) pyridin-2-yl ] (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [ 3.2-1 ] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [ 2-chloro-6-methoxypyridin-2-yl) (3- { [ 2-chloro-3-yl) imidazo [ 3.1, 2-a ] pyrimidin-8-yl ] methanone, 2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) pyrimidin-3-yl) oct-2-yl } -2, 5-diazabicyclo [2.2.2] oct-yl) methanone, (1, 2-oxa-2.2 ] oct-2-yl) methanone, 6-methoxy-3-methylpyridin-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) (2-fluorophenyl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.2.1] pyrimidin-8-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [ 3.1, 2-a ] pyrimidin-yl ] methyl } -3- { [ 2-methyl } -3-oxa-yl) imidazo [ 3.1-a ] methyl, 8-diazabicyclo [3.2.1] oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [6- (methylsulfanyl) pyridin-2-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (cyclopentyl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [6- (methylamino) pyridin-2-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 2-diaza-bicyclo [3.2.1] oct-8-yl) (3- { [ 2-methyl } -3- { [ 2-a ] pyrimidin-3-yl) methyl } -3, 2-diaza-bicyclo [3.2.1] oct-8-yl ] methyl } -3-2-yl ] pyrimidin-3-yl ] methanone, 5-diazabicyclo [2.2.2] oct-2-yl) (cyclopentyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [ 2.2-2 ] oct-3-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] 2-yl ] methyl } -2-fluoro-imidazo [ 2.2-2 ] 2-yl ] oct-2-yl) methanone, 5-diazabicyclo [2.2.2] oct-2-yl) (2-fluorophenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-methoxyphenyl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (7- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl ] methyl } -3-oxazolo [ 3-yl ] (3- { [ -chloro-6-methoxypyridin-2-yl) methanone, 2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (2-cyclopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (5-methyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (5-isopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3- { [2, 2-a ] pyrimidin-3-yl) methyl } -3, 8-imidazo [3, 2.1] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3, 3-chloro-oxazol-3-yl) methanone, 3-oxazol-4-yl) methanone, (4-bromo-5-methyl-1, 3-thiazol-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (5-cyclopropyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (2-isopropyl-1, 3-thiazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 3- { [ 2-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-3-yl ] (3-chlorophenyl) 1, 3-oxazol-3-yl) methanone, 2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (2, 5-dimethyl-1, 3-oxazol-4-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [ 2-methoxy-4- (trifluoromethyl) -1, 3-thiazol-5-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [2- (trifluoromethyl) -1, 3-thiazol-4-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [1,2-a ] pyrimidin-3-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [ 3.2.1-a ] pyrimidin-3-yl ] methanone, 8-diazabicyclo [3.2.1] oct-8-yl) [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (1, 3-thiazol-4-yl) methanone, (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [6- (methylamino) pyridin-2-yl ] methanone, (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-isopropylphenyl) imidazo [1, 2-1 ] oct-8-yl) imidazo [3- (3-methylamino) pyridin-2-yl ] (3- { [ 2-1, 2-a ] imidazo [ 3-yl) imidazo [1, 2-1-yl ] (3- { [ 2-diaza-1-2.1 ] oct-8-yl) methanone, 2-a ] pyrimidin-3-yl ] ethyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) methanone, (2-fluorophenyl) (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3-oxo-7, 9-diazabicyclo [ 3.1-yl ] non-3-yl) methyl } -3-fluoro-6-methoxypyridin-2-yl) (7- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-9-yl) methanone, (3-fluoro-6-methylpyridin-3-yl) methyl } -3-fluoro-7, 9-diazabicyclo [ 3.1-yl ] pyrimidin-3-yl-methyl-yl, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (5-cyclopropyl-1, 3-oxazol-4-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (5 { [2 x (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -, 2,5 x diazabicyclo [ 2.2.2.2 ] oct-2 ] methanone, (5- { [2- (4-isopropylphenyl) imidazo [1, 2-2 ] pyrimidin-3-yl) methyl } -2, 5-diazabicyclo [2.2.2] 2] methyl } -2-azolo- [2.2 ] methyl ] - [ 3-fluoro-6-methoxypyridin-2-yl) methanone, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxypyridin-2-yl) methanone, [6- (difluoromethoxy) pyridin-2-yl ] (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxy-3-methylpyridin-2-yl) methanone, (5- { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (2-fluorophenyl) methanone, (5- { [ 2-bromo-2.2-a ] pyrimidin-3-yl) methyl } -2,5- { [ 2-bromo-2-methyl } -2-oxa-2-yl) (1, 2-bromopyrimidin-2-yl) methanone, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3 { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } - [3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3- { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (2-fluorophenyl) methanone, (3- { [2- (4-bromophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (cyclopentyl) methanone, 3- { [2- (4-fluoro-6-methoxypyridin-2-yl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-cyclopropyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 5-dichloro-4-methoxyphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, N- (3-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 6-difluoro-8-carboxamide, N- (3-chlorophenyl) -3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [ 2-a ] imidazo [ 3-yl ] methyl } -N- (2, 6-difluoro-2.1-chloro-1-chloro-2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [ 3.1-2.1 ] methyl ] carboxamide 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 6-dimethylphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2-fluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 3-dichlorophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2-ethylphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, N- (2-chlorophenyl) -2- { [ 2-imidazo [3.2.1] pyrimidin-yl ] methyl } -N- (2-chlorophenyl) -3, 8-imidazo [3, 2-chlorophenyl ] imidazo [ 3.1-yl ] methyl } -N- (2-chlorophenyl) -3- { [ 2-imidazo [3.2.1] methyl ] -3- { [ 2-chlorophenyl ] imidazo [ 3.1-yl ] methyl } -N- (2-chlorophenyl) -3-naphthyridinyl ] -1-2-yl-naphthyridone, 2-a ] pyrimidin-3-yl ] methyl } -N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2-ethyl-6-methylphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 5-dimethylphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-cyclohexyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-a ] pyrimidin-3-yl ] methyl } -N- (2, 5-dimethylphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 4-dimethoxyphenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- {4- [ (trifluoromethyl) thio ] phenyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (3-fluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (2, 6-difluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (3-chlorophenyl) imidazo [ 3.2-1 ] methyl ] -3- { [2- (4-chlorophenyl) imidazo [3.2.1] pyrimidin-3-yl ] methyl } -N- { [2- (4-chlorophenyl) imidazo [3.2.1] methyl ] -3- { [2- (3-chlorophenyl) imidazo [ 3.1-a ] pyrimidin-3-yl ] methyl } -N- (3-chlorophenyl) imidazo [ 3.1-yl ] methyl ] - [ 3-2.1-2-2.1 ] pyrimidine-3-carboxamide, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-methyl-N-phenyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N, N-diethyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (morpholin-4-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N, N-diisopropyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N, N-diaza-3, 2-chloro-imidazo [ 3.1] 2-yl ] methyl } -N- { [ 2-diaza-3-yl ] imidazo [ 3.1, 2.1] octa-yl ] (3- { [ 2-chlorophenyl) imidazo [ 3.1-methyl ] carboxamide, 2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (pyrrolidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-ethyl-N-phenyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-isopropyl-N-methyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (piperidin-1-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N-isopropyl-N-methyl-3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl } -3- { [2- (4-chlorophenyl) imidazo [ 3.1-methyl-8-aza-bicyclo [ 3.1-a ] pyrimidin-8-yl ], 2-a ] pyrimidin-3-yl ] methyl } -N-isopropyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N, N-dimethyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (4-ethoxyphenyl) -N-methyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- (3-methoxybenzyl) -N-methyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxamide, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -N- { [2- (4-chlorophenyl) imidazo [3.2.1] methyl } -3- { [ 2-diazabicyclo [ 3.1] methyl ] 2-carboxamide, 3- { [2- (4-chlorophenyl) imidazo [ 3.1, 2.1] methyl ] morpholin-8-carboxamide, 8-diazabicyclo [3.2.1] octane-8-carboxylate, ethyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, cyclopentyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, propyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, cyclohexylmethyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, cyclohexyl 3- [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-bicyclo [3.2.1] octane-8-carboxylate, propyl 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 3- { [2- (4-chlorophenyl) imidazo [ 3.1, 2-a ] methyl } -3, 2-diaza-2.1 ] 2-carboxylate Tert-butyl 3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, (5-cyclopropyl-1, 3-oxazol-4-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, tert-butyl 3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (2-fluorophenyl) methanone, 3- { [2- (4-cyclopropyl-phenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl } -3- { [ 2-methyl } -3- { [ 2-oxa 2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1, 1] methyl- ], 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) [6- (difluoromethoxy) pyridin-2-yl ] methanone, (3- { [2- (4-cyclopropylphenyl) pyrimidin-3-yl) methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (3-cyclopropylphenyl) oct-8-yl) methyl } -3, 8-diazabicyclo [ 3.1-yl ] pyrimidin-3-yl ] methyl } -3-2-yl) 2-methyl } -3- { [ 2-oxa-2-1-yl ] methyl-2-yl Tert-butyl 6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] nonane-2-carboxylate, (-) -tert-butyl 6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] nonane-2-carboxylate, tert-butyl 9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonane-3-carboxylate, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] decan-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonane-3-yl ] methyl } -3- { [ 2-yl ] imidazo [1, 2.1] imidazo [1,2-a ] pyrimidin-3-yl ],10-yl, 2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (4-amino-1, 2-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] non-3-methyl } -2, 6-imidazo [ 3.2-yl ] pyrimidin-3-yl ] methyl } -2, 6-imidazo [ 3.2.2-yl ] imidazo [1,2-a ] pyrimidin-3-yl ] (2-chlorophenyl) imidazo [ 3.2.2-yl ] methanone, [ 4-amino-3-2-oxadiazol-3-yl ], 2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (4-amino-1, 2, 5-oxadiazol-3-yl) [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [ 3.2-a ] pyrimidin-3-yl ] methyl } -2, 6-triazol-2-yl ] imidazo [1,2-a ] pyrimidin-3-yl } -2, 6-diazabicyclo [ 3.2-yl ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [ 3.2.2-yl ] methyl } -2, 6-imidazo [ 3.2-a ] non-yl ] methanone (3-fluoro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, cyclopentyl [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-yl ] methanone, [6- (difluoromethoxy) pyridin-2-yl ] [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [ 3.2.2.2 ] non-yl ] methanone, (3- { [ 2-a ] pyrimidin-3-yl ] methyl } -2, 6-diaza-bicyclo [ 3.2.2.2-yl ] non-2-yl ] methanone, and (3-isopropylphenyl) imidazo [ 3.2.2.2 ] non-yl ] methyl } -2-fluoro-6-naphthyridin-3- (4-isopropylphenyl) pyrimidin-3-yl ] methyl-yl ] methanone (2-fluorophenyl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] (6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (3-chloro-6-methoxypyridin-2-yl) [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] } -methyl } -2, 6-diaza pyridin-2-yl ] [ 3-fluoro-2-yl ] [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [ 3.2.2-yl ] [ 2-methyl ] [ 3-fluoro-1, 2-a ] imidazo [ 2-yl ], 6-diazabicyclo [3.2.2] non-2-yl ] methanone, cyclopentyl [6- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] methanone, (3-fluoro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, (3-chloro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-yl ] methyl } -3, 9-fluoro-3-isopropyl) 1, 2-triazol-3-yl ] [ 3-chloro-6-methoxypyridin-2-yl ] [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methanone, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, cyclopentyl [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, (3-fluoro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, (3-chloro-6-methoxypyridin-2-yl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-yl ] methyl } -3, 9-fluoro-3-isopropyl) 1, 2-methyl ] [ 3-chloro-6-methoxypyridin-2-yl ] [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methanone, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, cyclopentyl [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, (-) - (2-fluorophenyl) [9- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-3-yl ] methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 6-diazabicyclo [3.2.2] non-2-yl ] [6- (trifluoromethoxy) pyridin-2-yl ] methanone, [6- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [ 4.2-yl ] imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 6-diaza-bicyclo [1,2-a ] pyrimidin-3-yl ] methanone, [6- { [2- (4-chlorophenyl) imidazo [3, 2-a ] methyl ] -3-2-difluoro ] imidazo [ 2-yl ] pyridin-3-yl ] methanone, and [6- { [ 2-1, 2-a ] imidazo [ 3-yl ] methyl } -3, 2-difluoro ] 1, 2-yl ] imidazo [1,2-a ] pyrimidin-3-yl ] methanone [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] dec-10-yl ] (6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] dec-10-yl ] (4-methyl-1, 2, 5-oxadiazol-3-yl) methanone, (4-amino-1, 2, 5-oxadiazol-3-yl) [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] dec-10-yl ] methanone, [3- { [2- (4-chlorophenyl) imidazo [4.3.1] dec-10-yl ] (4-methyl-1, 2, 5-oxadiazol-3-yl) [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methanone, [3- { [2- (4-chlorophenyl) imidazo [1, 3.1] dec-10-yl ] - [3- { [ (3-methyl) 1-2-oxadiazol-3-yl ],3-yl), 9-diazabicyclo [4.2.1] non-9-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-9-yl ] (6-methoxypyridin-2-yl) methanone, [ [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] dec-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -3, 6-diazabicyclo [3.2.2] non-6-yl ] (3-fluoro-6-methoxypyridin-3-yl) methyl } -8-fluoro-3-2-a ] pyrimidin-3-yl ] [ 3-fluoro-6-methoxypyridin-3-yl ] methyl } -3- { [ 2-1, 2-1-yl ] decan-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, 2-a ] pyrimidin-3-yl ] methyl } -3, 6-diazabicyclo [3.2.2] non-6-yl ] (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-9-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone, (3-fluoro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-9-yl ] methyl } -3, 9-imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-imidazo [ 4.2-yl ] imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone (3-chloro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone.
In a more preferred embodiment of the invention, the following combinations are involved: a compound of formula (I) selected from:
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin-1 ' -yl ] -1' -yl, 3-thiazole-5-carboxamide
A compound of formula (II) selected from:
(4- { [2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (2-fluorophenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-isopropoxypyridin-2-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (4- { [ 2-yl) methanone, 2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) [6- (trifluoromethoxy) pyridin-2-yl ] methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-2-yl) methanone, [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-3-yl) methanone, 2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxy-3-methylpyridin-2-yl) methanone, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl ] (6-methoxypyridin-2-yl) methanone, (-) - (3-chloro-6-methoxypyridin-2-yl) [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl ] methanone, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2,5- { [ 2-dichloro-2-yl ] (2-chloro-6-methoxypyridin-2-yl) imidazo [1, 2-yl ] (2-chloro-1-chloro-2-yl) imidazo [ 2-1, 2-yl ] (2-chloro-2-fluoro) imidazo [ 2-yl ],1-2- { [ 2-methyl ], 2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone (-) - (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) [6- (difluoromethoxy) pyridin-2-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-yl) methanone, 3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) methanone, 5- { [ 2-isopropyl ] imidazo [ 3.2.2.2 ] oct-yl ] methyl } -3-2-yl ] methanone (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [3.2.1] oct-8-yl ] methyl } -3- { [ 2-fluoro-6-methoxypyridin-2-yl) methanone, 10-diazabicyclo [4.3.1] dec-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-9-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone.
In a most preferred embodiment, the present invention relates to a combination of: a compound of formula (I) selected from:
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin-1 ' -yl ] -1' -yl, 3-thiazole-5-carboxamide
A compound of formula (II) selected from:
(3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, 2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, 3- { [2- (4-cyclopropylphenyl) pyrimidin-3-yl ] oct-8-yl) methanone, 3- { [2- (3-chloro-6-methoxypyridin-2-yl) methanone, 3- { [2- (4-cyclopropylphenyl) imidazol-3-yl ] oct-8-yl ] methyl } -3, 8-diazabicyclo [3.2.1] methoxy-8-yl ] methanone 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [4.3.1] dec-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone.
Another preferred embodiment of the invention relates to a combination of: a compound of formula (I) selected from:
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin-1 ' -yl ] -1' -yl, 3-thiazole-5-carboxamide
A compound of formula (II) selected from:
(4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, and (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [ 3.2.1-yl ] methanone.
Another preferred embodiment of the invention relates to a combination of: a compound of formula (I) selected from:
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin-1 ' -yl ] -1' -yl, 3-thiazole-5-carboxamide
A compound of formula (II) selected from:
(4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, and (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone.
Another preferred embodiment of the invention relates to a combination of the following compounds:
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
And (3) with
(4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone.
Another preferred embodiment of the invention relates to a combination of the following compounds:
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
And (3) with
(3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone.
The terms used herein have the meanings shown below. The term "at least one" is used in the following sense to mean one or several, such as one.
The term "hydroxy", as used herein either by itself or as part of another group, refers to an-OH group.
In the context of the present invention, 1 6 (C-C) -alkylIs a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.
In the context of the present invention, 1 4 (C-C) -alkylIs a straight or branched alkyl group having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
In the context of the present invention, 1 3 (C-C) -alkylIs a straight or branched alkyl group having 1 to 3 carbon atoms. Examples include: methyl, ethyl, n-propyl and isopropyl.
Terminology 1 6 (C-C) alkoxyAs used herein, either by itself or as part of another group, means (C) 1 -C 6 ) The alkyl group is appended to the parent molecular moiety through an oxygen atom. (C) 1 -C 6 ) Representative examples of alkoxy groups includeBut are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-dimethylpropoxy, 3-methylbutoxy and n-hexyloxy.
The term'Halogen-free food"OR"Halogen (halogen)", as used herein by itself or as part of another group, refers to fluorine, chlorine, bromine, or iodine.
In the context of the present invention, 1 3 mono- (C-C) -alkylaminoIs an amino group having a linear or branched alkyl substituent of 1 to 3 carbon atoms. Examples include: methylamino, ethylamino, n-propylamino and isopropylamino.
In the context of the present invention, 1 3 di- (C-C) -alkylaminoIs an amino group having two identical or different linear or branched alkyl substituents each having from 1 to 3 carbon atoms. Examples include: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-methylamino, N-di-N-propylamino, N-isopropyl-N-N-propylamino and N, N-diisopropylamino.
In the context of the present invention, 1 3 (C-C) -alkylthio[ also referred to as (C) 1 -C 3 ) Alkylthio groups]Is a straight or branched alkyl group having 1 to 3 carbon atoms which are linked to the remainder of the molecule via one sulfur atom. Examples include: methylthio, ethylthio, n-propylthio and isopropylthio.
In the context of the present invention, 3 6 (C-C) -cycloalkylIs a monocyclic saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In the context of the present invention, 4 6 (C-C) -cycloalkylIs a monocyclic saturated cycloalkyl group having 4 to 6 carbon atoms. Examples include: cyclobutyl, cyclopentyl, and cyclohexyl.
Terminology 1 6 Hydroxy (C-C) alkyl As per se hereinOr as part of another group, means that at least one hydroxyl group as defined herein is reacted with a hydroxyl group as defined herein through a (C 1 -C 6 ) Alkyl groups are appended to the parent molecular moiety. Hydroxy (C) 1 -C 6 ) Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and 1-hydroxy-1-methylpropyl.
Terminology 1 6 1 6 (C-C) alkoxy (C-C) alkylAs used herein, by itself or as part of another group, means at least one (C) 1 -C 6 ) Alkoxy is represented by a radical (C) 1 -C 6 ) Alkyl groups are appended to the parent molecular moiety. There are several (C) 1 -C 6 ) Alkoxy, the said (C 1 -C 6 ) The alkoxy groups may be the same or different.
1 6 1 6 (C-C) alkoxy (C-C) alkylRepresentative examples of (a) include, but are not limited to: methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl and 4-methoxybutyl.
Terminology 1 6 Hydroxy (C-C) alkoxyAs used herein, by itself or as part of another group, means that at least one hydroxyl group as defined herein is reacted with a hydroxyl group as defined herein through a (C 1 -C 6 ) Alkoxy groups are appended to the parent molecular moiety. Hydroxy (C) 1 -C 6 ) Representative examples of alkoxy groups include, but are not limited to, hydroxymethyl, dihydroxymethoxy, dihydroxyethoxy, dihydroxypropoxy, trihydroxypropoxy, dihydroxybutoxy, and dihydroxy-1-methylethoxy.
Terminology 1 6 1 6 (C-C) alkoxyAs used herein either by itself or as part of another groupRefers to at least one (C) as defined herein 1 -C 6 ) Alkoxy is represented by a radical (C) 1 -C 6 ) Alkoxy groups are appended to the parent molecular moiety. Said (C) 1 -C 6 ) The alkoxy groups may be the same or different. (C) 1 -C 6 ) Alkoxy (C) 1 -C 6 ) Representative examples of alkoxy groups include, but are not limited to, methoxymethoxy, propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy, 2-dimethoxyethoxy, 1-methyl-2-propoxyethoxy, 2-methoxypropoxy and 4-methoxybutoxy.
Terminology 1 6 Halo (C-C) alkoxyAs used herein, by itself or as part of another group, means that at least one halogen as defined herein is reacted with a halogen as defined herein through a moiety (C 1 -C 6 ) Alkoxy groups are appended to the parent molecular moiety. When there are several halogens, the halogens may be the same or different. Halo (C) 1 -C 6 ) Representative examples of alkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, trifluoromethoxy, 2-bromoethoxy, 2-trichloroethoxy, 3-bromopropoxy, 2-chloropropoxy, and 4-chlorobutoxy.
The expression "compounds of the invention" as used herein refers to compounds of formula I.
Pharmaceutically acceptable salts, such as acid addition salts comprising organic and inorganic acids, are known in the pharmaceutical arts. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chloride, bromide, sulfate, nitrate, phosphate, sulfonate, mesylate, formate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate, acetate, and oxalate.
According to the present invention, hydrates or solvates are designated as those forms of the compounds of formula (I) that hydrate with water or coordinate with solvent molecules in the solid or liquid state to form molecular compounds or complexes. Examples of hydrates are sesquihydrate, monohydrate, dihydrate or trihydrate. Also suitable are hydrates or solvates of salts of the compounds of the invention.
Pharmaceutically acceptable esters, if appropriate, can be prepared by known methods using pharmaceutically acceptable acids which are conventional in the pharmaceutical arts and which retain their pharmacological effect in free form. Non-limiting examples of such esters include esters of aliphatic alcohols or esters of aromatic alcohols. Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl esters.
The present invention includes within its scope all possible geometric isomers of the compounds, such as Z and E isomers (cis and trans isomers), as well as all possible optical isomers of the compounds, such as diastereomers and enantiomers. Furthermore, the present invention includes within its scope individual isomers as well as any mixtures thereof, such as racemic mixtures. The individual isomers may be obtained using starting materials having the corresponding isomeric forms, or may be isolated following conventional isolation procedures after preparation of the final compound. For separating optical isomers, such as enantiomers, from a mixture thereof, a conventional resolution method such as fractional crystallization may be used.
Compounds of formula (II), their preparation and their use as selective blockers of the TASK-1 and TASK-3 channels or in the treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders are generally disclosed in WO 2017/097792 A1, WO 2018/015196 A1, WO 2018/228907 A1 and WO 2018/228909 A1, and in particular are specifically a clear part of the present specification and are hereby incorporated by reference.
The term "effective amount" as used herein refers to an amount of a compound of formula (I) effective to treat and/or prevent sleep-related respiratory disorders, preferably obstructive and central apneas, as well as snoring.
The present invention relates to the use of a combination of a compound of formula (I) and a compound of formula (II) according to the invention in a method for the treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders.
The invention also relates to the use of a combination of a compound of formula (I) according to the invention and a compound of formula (II) for the preparation of a medicament for the treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders, preferably obstructive and central sleep apnea and snoring.
Furthermore, the present invention relates to the use of one or more selective blockers of TASK-1 and TASK-3 channels in combination with one or more alpha 2-adrenoreceptor subtype C (alpha-2C) antagonists for the manufacture of a pharmaceutical composition for the treatment of sleep-related breathing disorders.
A further subject of the invention is the use of a combination of a compound of formula (I) according to the invention with a compound of formula (II) and one or more other active compounds in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.
Another subject of the invention is a medicament comprising at least one compound of formula (I) according to the invention in combination with a compound of formula (II) in combination with one or more inert non-toxic pharmaceutically suitable excipients for use in a method for the treatment and/or prophylaxis of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
The invention also relates to a medicament comprising at least one compound of formula (I) according to the invention in combination with a compound of formula (II) in combination with one or more other active compounds in combination with one or more inert non-toxic pharmaceutically suitable excipients for use in a method for the treatment and/or prophylaxis of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
The invention also relates to a method for the treatment and/or prophylaxis of sleep-related breathing disorders by systemic and/or local administration of an effective amount of at least one compound of formula (I) in combination with a compound of formula (II) or a medicament comprising at least one compound of formula (I) according to the invention in combination with a compound of formula (II) in combination with inert, non-toxic, pharmaceutically acceptable additives.
The combination of a compound of formula (I) and a compound of formula (II) according to the invention may be used alone or in combination with one or more other pharmaceutically active substances if desired, provided that the combination does not lead to undesired and unacceptable side effects. Preferred examples of combinations suitable for this purpose for the treatment of sleep related respiratory diseases, preferably obstructive and central sleep apnea and snoring include:
Respiratory stimulants such as, and preferably, theophylline (theophylline), doxapram (doxapram), niketamide (nikethamide), or caffeine (caffeine);
psychostimulants, such as and preferably modafinil (modafinil) or aj Mo Feini (armafinil);
amphetamine and amphetamine derivatives, such as and preferably amphetamine, methamphetamine (methamphetamine) or methylphenidate;
serotonin reuptake inhibitors such as, and preferably, fluoxetine (fiuoxetine), paroxetine (paroxetine), citalopram (citalopram), escitalopram (escitalopram), sertraline (sertraline), fluvoxamine (fluvoxamine) or trazodone;
serotonin precursors, for example and preferably L-tryptophan;
a selective serotonin norepinephrine reuptake inhibitor, such as, and preferably, venlafaxine (venlafaxine) or duloxetine (duloxetine);
noradrenergic and specific serotonergic antidepressants, for example and preferably mirtazapine (mirtazapine);
selective norepinephrine reuptake inhibitors such as, and preferably, reboxetine (reboxetine) or atomoxetine (atomoxetine);
tricyclic antidepressants such as, but preferably, amitriptyline, protirine, doxepin, trimipramine, imipramine, clomipramine or desipramine;
Muscarinic receptor antagonists such as, and preferably, oxybutynin (oxybutynin);
GABA agonists such as, and preferably, baclofen (baclofen);
glucocorticoids, for example and preferably fluticasone (fluticasone), budesonide, beclomethasone (beclomethasone), mometasone (mometasone), tixocortol (tixocortol) or triamcinolone (triamcinolone);
cannabinoid receptor agonists;
carbonic anhydrase inhibitors, for example and preferably acetazolamide (acetozolamide), methazolamide (methazolamide) or diclofenamide (dichlofenamide);
opioid and benzodiazepine (benzodiazepine) receptor antagonists, for example and preferably flumazenil (flumazinil), naloxone (naloxone) or naltrexone (naltrexone);
cholinesterase inhibitors such as, and preferably, neostigmine, pyristigmine, physostigmine donepezil (physostigmine donepezil), galantamine or rivastigmine;
appetite suppressants, such as and preferably sibutramine (sibutramine), topiramate (opiramide), phentermine (phentermine), lipase inhibitors (lipase inhibitors) or cannabinoid receptor antagonists;
Mineralocorticoid receptor antagonists.
A medicament comprising a conjugate as defined in any one of claims 1 to 5 in combination with one or more other active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.
A preferred subject of the invention is a combination comprising a compound of formula (I) according to the invention in combination with a compound of formula (II) and one or more further active compounds selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids, for use in a method of treatment and/or prophylaxis of sleep-related respiratory diseases, preferably obstructive and central apneas and snoring.
Another preferred subject of the invention is a medicament comprising a combination of a compound of formula (I) according to the invention and a compound of formula (II) in combination with one or more further active compounds selected from muscarinic receptor antagonists.
In a preferred embodiment of the invention, the conjugate of the invention is administered in combination with a muscarinic receptor antagonist (e.g. and preferably oxybutynin).
In a preferred embodiment of the invention, the conjugate of the invention is administered in combination with a mineralocorticoid receptor antagonist, for example and preferably spironolactone (spironolactone), eplerenone (eplerenone) or finrenone (finerenone).
In a preferred embodiment of the invention, the conjugate of the invention is administered in combination with a diuretic, for example and preferably furosemide (furosemide), bumetanide (bumetanide), torsemide (torsemide), benfurosemide (benfuramethazine), chlorthiazide (chlorthiazide), hydrochlorothiazide (hydrochlorothiazide), hydrochlorothiazide (hydro-thiazide), methyl-chlorthiazide (methyhazide), poise Li Sai zine (polymethide), trichlorethiazide (trichlorethamine), chlorthalidone (chlorthalide), indapamide (medazone), quinethazone (quinethazine), acetyl oxazolone (acetozolide), dichlorophenazine (dichlorphenamide), mannitol (methylene chloride), mannitol (trimethazine), or glycerin (trimethoprim).
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid, such as, and preferably, prednisone (prednisone), prednisolone (prednisolone), methylprednisolone (methylprednisolone), triamcinolone (triamcinolone), dexamethasone (dexamethasone), betamethasone (betamethasone), beclomethasone (beclomethasone), flunisolide (flunisolide), budesonide (budesonide) or fluticasone (fluticasone).
The arylpiperazines of formula (I) of the present invention may also be used in combination with one or more medical-technical devices or aids, if desired, provided that they do not cause unwanted and unacceptable side effects. Medical devices and aids suitable for such combined applications, for example and preferably:
positive airway pressure devices such as, and preferably, CPAP (continuous positive airway pressure) devices, biPAP (bi-level positive airway pressure) devices, and IPPV (intermittent positive airway pressure) devices;
neural stimulator of neural prolapse;
intraoral auxiliary devices such as and preferably protruding braces (protrasion braces);
nasal disposable valve;
nasal stent.
The substituted heterocyclic carboxamides of the formula (I) and the compounds of the formula (II) according to the invention can act systemically and/or locally. For this purpose, they may be administered in a suitable manner, for example by the oral, parenteral, pulmonary, intrapulmonary (inhaled), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auditory canal route, or as implants or stents.
Another subject of the invention is a pharmaceutical composition comprising a combination of a compound of formula (I) and a compound of formula (II) for systemic and/or local administration by the following route: oral, parenteral, pulmonary, intrapulmonary (inhaled), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or aural routes, or as implants or stents. Preferred administration is oral and pharyngeal route.
For these routes of administration, the compounds of the present invention may be administered in a suitable form of administration.
For oral administration, administration forms which act according to the prior art to release the compounds of the invention rapidly and/or in an improved manner are suitable, which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolution or insoluble coatings which control the release of the compounds of the invention), tablets or films/wafers which disintegrate rapidly in the oral cavity, films/lyophilisates or capsules (for example hard or soft gelatine capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration may be effected by omitting the step of absorption (e.g., by intravenous, intra-arterial, intra-cardiac, intraspinal or intra-lumbar administration) or by including the step of absorption (e.g., by intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Forms of administration suitable for parenteral administration include injectable and infusible preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
For other routes of administration, suitable are, for example, inhalable pharmaceutical forms (including powder inhalers and nebulizers), nasal drops, solutions or sprays, pharyngeal sprays, tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, oral or ophthalmic preparations, vaginal capsules, aqueous suspensions (emulsions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), emulsions (milk), pastes, foams, withdrawal powders, implants or stents.
Oral or nasal and pharyngeal administration is preferred.
The compounds of the present invention may be converted into the administration forms described. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable additives. These additives include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), dyes (e.g. inorganic pigments, e.g. iron oxide) and flavouring and/or odour-correcting agents.
Generally, for effective results in oral administration, it has been found advantageous to administer amounts of about 0.01 to 100mg/kg, preferably about 0.01 to 10mg/kg body weight. In nasal or pharyngeal administration, the dosage is about 0.01 μg/kg to 1000 μg/kg, preferably about 0.1 to 10 μg/kg body weight. However, in some cases it may be necessary to deviate from the prescribed amounts, i.e. depending on the body weight, the route of administration, the individual response to the active substance, the nature of the formulation and the time or time interval of administration. Thus, in some cases it may be sufficient to use less than the minimum amount described above, while in other cases the upper limit specified must be exceeded. In the case of administration in relatively larger amounts, it is recommended that they can be divided into several separate administrations during the day.
Another subject of the invention is the combination of systemic administration of a compound of formula (I) with topical administration of a compound of formula (II).
For this purpose, the compounds of formula (I) may be administered in a suitable manner, for example by oral, parenteral, pulmonary, intrapulmonary (inhaled), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auditory canal route, or as implants or stents, and the compounds of formula (II) may be administered, for example, by nasal, intranasal, pharyngeal, lingual, sublingual and buccal routes.
Preferred routes of administration are the oral route of the compound of formula (I) and the nasal and pharyngeal route of the compound of formula (II).
For oral administration, administration forms which act according to the prior art to release the compounds of the invention rapidly and/or in an improved manner are suitable, which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolution or insoluble coatings which control the release of the compounds of the invention), tablets or films/wafers which disintegrate rapidly in the oral cavity, films/lyophilisates or capsules (for example hard or soft gelatine capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
For nasal and pharyngeal administration routes, such as nasal drops, solutions or sprays, pharyngeal sprays, tablets, films/wafers or capsules, suppositories or oral formulations for lingual, sublingual or buccal administration are suitable.
The following examples illustrate the invention. The present invention is not limited to these examples.
Examples
The synthesis of compounds of formula (I) is described in this section.
Abbreviations and acronyms:
abs. Absolute value
Ac acetyl group
aq. aqueous solution
Boc
br. wide (in NMR signal)
Ex. Examples
Bu butyl
concentration of c
cat. Catalysis
CI chemical ionization (in MS)
d bimodal (in NMR)
day d
DCI direct chemical ionization (in MS)
dd double bimodal (in NMR)
Mixtures of diamix diastereoisomers
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
dq double quartet (in NMR)
dt double trimodal (in NMR)
Theoretical (in chemical yield)
EI electron impact ionization (in MS)
eq. Equivalent weight
ESI electrospray ionization (in MS)
Et ethyl group
h hours
HATU O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate
HOBt 1-hydroxy-1H-benzotriazole hydrate
HPLC high pressure high performance liquid chromatography
iPr isopropyl group
conc. Concentrated (in the case of solutions)
LC liquid chromatography
LC-MS liquid chromatography-mass spectrometry
lit literature (ref)
m multiple peaks (in NMR)
Me methyl group
min
MS mass spectrometry
NMR spectroscopy
Ph phenyl
Pr propyl group
q quartet (in NMR)
quant quantitative (in chemical yield)
RP reversed phase (in HPLC)
RT room temperature
R t Retention time (in HPLC, LC/MS)
s single peak (in NMR)
t triplet (in NMR)
tBu t-butyl
TFA trifluoroacetic acid
THF tetrahydrofuran
UV spectroscopy
v/v (volume/volume ratio of solution)
tog together
LC-MS, GC-MS and HPLC methods
Method 1 (LC-MS):
MS instrument type: thermo Scientific FT-MS; instrument type uhplc+: thermo Scientific UltiMate 3000; column: waters, HSST3,2.1x75mm, c181.8 μm; mobile phase: 1 liter of water +0.01% formic acid; mobile phase B:1 liter of acetonitrile +0.01% formic acid; gradient: 0.0min 10% B→2.5min 95% B→3.5min 95% B; and (3) an oven: 50 ℃; flow rate: 0.90ml/min; UV detection: 210 nm/optimal integration path 210-300nm.
Method 2 (LC-MS):
MS instrument type: waters Tinstrument; UPLC instrument type: waters acquisition I-CLASS; column: waters Acquity UPLC HSS T3 1.8 μm 50X1mm; mobile phase: 1 liter of water +0.100ml of 99% strength formic acid; mobile phase B:1 liter of acetonitrile+0.100 ml of 99% strength formic acid; gradient: 0.0min 90% A→1.2min 5% A→2.0min 5% A; and (3) an oven: 50 ℃; flow rate: 0.40ml/min; UV detection: 210nm.
Method 3 (GC-MS):
instrument: thermo Scientific DSQII, thermo Scientific Trace GC Ultra; column: restek RTX-35MS,15 mX100.mu. m x 0.33.33. Mu.m; constant helium flow rate: 1.20ml/min; and (3) an oven: 60 ℃; sample inlet: 220 ℃; gradient: 60 ℃,30 ℃/min- & gt 300 ℃ (hold for 3.33 min).
Method 4 (LC-MS):
instrument: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8.8 μm 50x 1mm; mobile phase: 1 liter of water +0.25ml of 99% strength formic acid, mobile phase B:1 liter of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0min 90% A→1.2min5% A→2.0min 5% A; and (3) an oven: 50 ℃; flow rate: 0.40ml/min; UV detection: 210nm.
Method 5 (LC-MS):
instrument: waters Single Quad MS system; instrument Waters UPLC Acquity; column: waters BEH C181.7 μ 50x 2.1mm; mobile phase: 1 liter of water+1.0 ml (25% strength ammonia)/l, mobile phase B:1 liter of acetonitrile; gradient: 0.0min 92% A→0.1min 92% A→1.8min 5% A→3.5min 5% A; and (3) an oven: 50 ℃; flow rate: 0.45ml/min; UV detection: 210nm.
Method 6 (LC-MS):
MS instrument: waters SQD2 HPLC instrument: waters UPLC; column: z or bax SB-Aq (Agilent), 50mm x 2.1mm,1.8 μm; mobile phase: water +0.025% formic acid, mobile phase B: acetonitrile (ULC) +0.025% formic acid; gradient: 0.0min 98% A-0.9min 25% A-1.0min 5% A-1.4min 5% A-1.41min 98% A-1.5min 98% A; and (3) an oven: 40 ℃; flow rate: 0.600ml/min; UV detection: DAD;210nm.
Method 7 (preparative HPLC):
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100X30mm.
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection).
Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
Method 8 (preparative HPLC):
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100X30mm.
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection).
Gradient curve: mobile phase A0 to 2min 63ml, mobile phase B0 to 2min 7ml, mobile phase A2 to 10min from 63ml to 39ml and mobile phase B from 7ml to 31ml,10 to 12min0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
Method 9 (preparative HPLC):
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100X30mm.
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection).
Gradient curve: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
Method 10 (preparative HPLC):
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100X30mm.
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection).
Gradient curve: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min 39ml to 15ml and mobile phase B31 ml to 55ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
Method 11 (preparative HPLC):
instrument: abimed Gilson 305; column: reprosil C1810 μm,250mm x 30mm; mobile phase: water, mobile phase B: acetonitrile; gradient: 0-3min 10% B,3-27min 10% B.fwdarw.95% B,27-34.5min 95%B,34.5-35.5min 95% B.fwdarw.10% B,35.5-36.5min10% B; flow rate: 50ml/min; room temperature; UV detection: 210nm.
Method 12 (LC-MS):
instrument: waters ACQUITY SQD UPLC system; column: waters Acquity UPLCHSS T31.8.8 μm 50x 1mm; mobile phase: 1 liter of water +0.25ml of 99% strength formic acid, mobile phase B:1 liter of acetonitrile +0.25ml of 99% strength formic acid; gradient: 0.0min95% A.fwdarw.6.0 min5% A.fwdarw.7.5 min5% A; and (3) an oven: 50 ℃; flow rate: 0.35ml/min; UV detection: 210nm.
Other details:
hereinafter, it is described that 1 Tracing of coupling modes of H NMR signalsThe described is guided according to the visual appearance of the signals involved and does not necessarily correspond to a strict, physically correct interpretation. In general, the chemical shift refers to the center of the signal involved; in the case of a broad multiple peak, the interval is given.
Melting point and melting path, if given, are uncorrected.
In the case of reaction products obtained by grinding, stirring or recrystallisation, it is often possible to separate further amounts of the product from the respective mother liquors by chromatographic separation. However, unless only a large part of the total yield can be isolated in this step, a description of such chromatography will be omitted hereinafter.
All reactants or reagents for their preparation, not explicitly described below, are purchased from commonly available sources. For all other reactants or reagents whose preparation is not described hereinafter as well and which are not commercially available or obtained from sources other than generally available, reference is made to the publications describing their preparation.
Starting materials and intermediates:
example 1A
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540000901
50.24ml (288.41 mmol) of N, N-diisopropylethylamine are added to a solution of 20g (96.14 mmol) of 2-bromo-1, 3-thiazole-5-carboxylic acid and 29.21g (134.59 mmol) of 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride in 450ml of acetonitrile, the mixture is cooled to 0℃using an ice bath, and then 74.4ml (124.98 mmol) of a 50% strength solution of T3P (2, 4, 6-tripropyl-1,3,5,2,4,6-trioxotriphosphohexane 2,4, 6-trioxide) in ethyl acetate are added dropwise to the reaction solution. After the addition was completed, the reaction solution was warmed to room temperature and stirred at this temperature for 4 hours. About 250ml of water was then added to the solution. The resulting aqueous phase was then extracted 3 times with ethyl acetate. The combined organic phases were then filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was triturated with diethyl ether and then air-dried. This gives 27.3g (81.7 mmol, 85% of theory) of the desired product as a pale beige solid. The recovered mother liquor was evaporated to dryness under reduced pressure and the resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100g column; mobile phase: cyclohexane/ethyl acetate 9:1→gradient 15CV (cv=column volume) →cyclohexane/ethyl acetate 1:1). This gives an additional 2.1g (6.28 mmol, 6.5% of theory) of the title compound as a white solid.
1 H-NMR(600MHz，DMSO-d 6 ，δ/ppm)：4.59(d，2H)，7.90-7.95(m，1H)，8.27(s，1H)，8.48(d，1H)，9.32(br.t，1H)。
LC-MS (method 1): r is R t ＝1.38min；m/z＝333/335(M+H) + 。
In analogy to example 1A, the following compounds examples 2A to 8A were prepared from the starting materials described in each case:
Figure BDA0004107514540000911
Figure BDA0004107514540000921
Figure BDA0004107514540000931
example 9A
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (1, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540000941
2g (5.99 mmol) of 2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide are dissolved in 30ml of THF and 4.88g (14.96 mmol) of cesium carbonate are added. 1.29g (8.98 mmol) of 1, 4-dioxa-8-azaspiro [4.5] decane were then metered into the reaction solution, which was subsequently stirred at reflux temperature overnight. After cooling, the reaction mixture was directly applied to silica gel and purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 50g column; mobile phase: cyclohexane/ethyl acetate 85:15→gradient 15CV (cv=column volume) →ethyl acetate). The resulting product fractions were then combined, concentrated on a rotary evaporator and dried under reduced pressure. This gives 1.40g (3.53 mmol, 99% of theory) of the title compound as a pale beige solid.
1 H-NMR(600MHz，DMSO-d 6 ，δ/ppm)：1.71(t，4H)，3.56(t，4H)，3.92(S，4H)，4.53(br.d，2H)，7.84(s，1H)，7.89-7.94(m，1H)，8.47(d，1H)，8.74(t，1H)。
LC-MS (method 2): rt=0.73 min; m/z=397 (m+h) + 。
Example 10A
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540000942
2.3g (5.80 mmol) of N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (1, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -1, 3-thiazole-5-carboxamide are dissolved in 15ml of acetone and 15ml of semi-concentrated aqueous hydrochloric acid are added. The reaction solution was then stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and subsequently placed in water. The aqueous solution was then adjusted to pH 7 with saturated sodium bicarbonate solution. The precipitate obtained is filtered off with suction, repeatedly washed with water and dried under reduced pressure. This gives 1.96g (5.49 mmol, 95% of theory) of the title compound as a white solid.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 2.48-2.56 (t, 4H, part)Masked by DMSO), 3.82 (t, 4H), 4.54 (br.d, 2H), 7.89 (s, 1H), 7.90-7.94 (m, 1H), 8.48 (d, 1H), 8.78 (t, 1H).
LC-MS (method 1): rt=1.09 min; m/z=353 (m+h) + °
Example 11A
3- [ (3, 3-difluorocyclobutyl) methoxy ] pyridine
Figure BDA0004107514540000951
2g (21.03 mmol) of pyridin-3-ol are dissolved in 40ml of THF and 7.17g (27.34 mmol) of triphenylphosphine are added. The clear solution was then cooled to 0 ℃. To the resulting suspension was added 30ml of THF. To this suspension 5.53g (27.34 mmol) of diisopropyl azodicarboxylate was added and the mixture was stirred at this temperature for 5 minutes. 3.34g (27.34 mmol) of (difluorocyclobutyl) methanol dissolved in 10ml of THF are then added dropwise and the ice bath is removed after the addition has ended. After stirring at room temperature for about one hour, a clear yellow solution formed, at which temperature stirring was carried out overnight.
Then, water was added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, separated and filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was stirred with about 150ml of cyclohexane. The precipitated triphenylphosphine was then filtered off with suction and washed repeatedly with cyclohexane. The resulting filtrates were combined and concentrated to dryness under reduced pressure. This gives 3.69g (18.52 mmol, 88% of theory) of the title compound as a yellow oil. The resulting target compound was further reacted without further purification.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 2.42-2.55 (m, 2H, partially masked by DMSO), 2.55-2.64 (m, 1H), 2.68-2.78 (m, 2H), 4.11 (d, 2H), 7.30-7.36 (m, 1H), 7.37-7.43 (m, 1H), 8.18 (dd, 1H), 8.30 (d, 1H).
LC-MS (method 1): r is R t ＝1.12min；m/z＝200(M+H) + 。
Example 12A
3- [ (3, 3-Difluorocyclobutyl) methoxy ] piperidine acetate (1:1) (racemate)
Figure BDA0004107514540000952
2.5g (12.55 mmol) of 3- [ (3, 3-difluorocyclobutyl) methoxy are reacted]Pyridine was dissolved in 20ml glacial acetic acid and H-Cube (Thales Nano H-Cube Pro) TM -1.7) hydrogenation.
Reaction conditions:
catalyst: pd/C10%; solvent: glacial acetic acid; cylinder pressure: 80 bar hydrogen; flow rate: 1 ml/min; temperature: 80 ℃.
After the reaction was completed, the reaction mixture was concentrated to dryness. The resulting residue was dried at room temperature under reduced pressure overnight. This gave 4.2g of the title compound as a yellow oil. The target compound was further reacted without further purification.
GC-MS (method 3): r is R t ＝3.87min；m/z＝205(M-C 2 H 4 O 2 ) + 。
Example 13A
3- (difluoromethyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (racemate)
Figure BDA0004107514540000961
1g (4.29 mmol) of benzyl 4-oxopiperidine-1-carboxylate, 883mg (5.14 mmol) of 3- (difluoromethyl) piperidine hydrochloride (1:1) and 0.9ml (5.14 mmol) of N, N-diisopropylethylamine are taken up in 15ml of dichloromethane (additionally small amounts of
Figure BDA0004107514540000963
Molecular sieves were added to the reaction solution) and stirred at room temperature for 1 hour. 1.363g (6.43 mmol) of sodium acetoxyborohydride are then added, and the reaction mixture is stirred at room temperature overnight. Then separate outThe reaction mixture was filtered off, washed with dichloromethane, and the filtrate was washed twice with sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is finally separated off and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. This gives 1.39g (3.54 mmol, purity 89%, 83% of theory) of the title compound as a colorless transparent oil. The target compound was further reacted without further purification.
LC-MS (method 1): r is R t ＝1.04min；m/z＝353(M+H) + 。
In analogy to example 13A, the following compounds of examples 14A to 17A were prepared from the starting materials described in each case:
Figure BDA0004107514540000962
Figure BDA0004107514540000971
Figure BDA0004107514540000981
example 18A
rac-3- (hydroxymethyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540000982
Acetic acid (1.8 ml,32 mmol) was added to a solution of rac-4-oxopiperidine-1-carboxylic acid benzyl ester (5.00 g,21.4 mmol) and piperidin-3-ylmethanol (4.94 g,42.9 mmol) in 50ml dichloromethane and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (5.45 g,25.7 mmol) was then added to the reaction and stirring continued at room temperature. After 2 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. Organic matters are treatedThe phases were washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off with suction and the filtrate is concentrated, the residue is applied to
Figure BDA0004107514540000993
Then pass through column chromatography
Figure BDA0004107514540000994
Isolera One; column: snap Ultra 100g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 4.37g (purity 100%, 61% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.92min；MS(ESIpos)：m/z＝333[M+H] + 。
Example 19A
rac-3- { [ (methylsulfonyl) oxy ] methyl } [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540000991
Rac-3- (hydroxymethyl) [1,4' -bipiperidine under argon]Benzyl-1' -formate (5.42 g,16.3 mmol) was initially taken in 65ml of dichloromethane, triethylamine (3.0 ml,21 mmol) was added and the mixture was cooled to 0 ℃. Methanesulfonyl chloride (1.5 ml,20 mmol) was added dropwise at this temperature. The mixture was then stirred at 0 ℃ for 15 minutes, after which the ice bath was removed and stirring continued at room temperature. After 15 minutes, the reaction mixture was diluted with dichloromethane and sequentially with 1N hydrochloric acid, saturated NaHCO 3 The solution and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated. The residue was dried under high vacuum and reacted further without further purification. This gives 6.16g (purity 100%, 92% of theory) of the target compound.
LC-MS (method 12): r is R t ＝1.39min；MS(ESIpos)：m/z＝411[M+H] + 。
Example 20A
rac-3- (methoxymethyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540000992
Sodium methoxide solution (840 μl,25% in methanol, 3.7 mmol) was added to rac-3- { [ (methylsulfonyl) oxy]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (500 mg,1.22 mmol) in 10ml DMF and the mixture was stirred overnight at 50 ℃. The solvent was removed on a rotary evaporator and the residue was dissolved in ethyl acetate and washed with water and then with saturated NaCl solution. The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated. Applying the residue to
Figure BDA0004107514540001003
And the mixture was purified by column chromatography (+.>
Figure BDA0004107514540001004
Isolera One; column: snap Ultra 25g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 75 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 146mg (purity 100%, 35% of theory) of the target compound.
LC-MS (method 4): rt=0.59 min; MS (ESIpos): m/z=347 [ m+h] + 。
Example 21A
diamix- (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001001
Acetic acid (1.71 ml,29.85 mmol) was added to a solution of rac-3-fluoro-4-oxopiperidine-1-carboxylic acid benzyl ester (5 g,19.9 mmol) and (3R) -3-methylpiperidine (5.4 g,39.8 mmol) in 200ml dichloromethane and mixedThe mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (5.06 g,23.88 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and sequentially saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated on a rotary evaporator. Applying the residue to
Figure BDA0004107514540001005
And by column chromatography (+)>
Figure BDA0004107514540001006
Isolera One; column: snap Ultra 100g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 5.13g (purity 55%, 42% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.05min；MS(ESIpos)：m/z＝335[M+H] + 。
Example 22A
diamix- (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -carboxylic acid tert-butyl ester
Figure BDA0004107514540001002
(3R) -3-methylpiperidine hydrochloride (6.24 g,46.0 mmol) was initially added to 250ml of 1, 2-dichloroethane. N, N-diisopropylethylamine (8.0 ml,46 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Rac-3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.00 g,23.0 mmol) and acetic acid (2.0 ml,35 mmol) were added and the mixture stirred at room temperature for 4h. Subsequently, sodium triacetoxyborohydride (5.85 g,27.6 mmol) was added, and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and sequentially saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated. Will remainThe material was purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XB ridge C18. Mu.m 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v), total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2 min 47ml, mobile phase B0 to 2 min 23ml, mobile phase A2 to 10 min from 47ml to 23ml, mobile phase B from 23ml to 47ml,10 to 12 min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were each at constant flow rates of 5 ml/min throughout the run time). The product-containing fractions were combined and concentrated on a rotary evaporator and the residue was dried under high vacuum. This gives 5.30g (purity 100%, 77% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.52min；MS(ESIpos)：m/z＝301[M+H] + 。
Example 23A
rac-3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001011
2, 2-trifluoroethanol (66. Mu.l, 910. Mu. Mol) was initially added to 5ml of DMF under argon and the mixture was cooled to 0℃in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred at 60 ℃. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was dried under high vacuum. This gives 218mg (purity 81%, 70% of theory) of the target compound.
LC-MS (method 1): rt=1.33 min; MS (ESIpos): m/z=415 [ m+h ]] + 。
Example 24A
rac-3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001021
Under argon, 1- (fluoromethyl) cyclopropyl]Methanol (95.1 mg, 913. Mu. Mol) was initially added to 5ml DMF and the mixture was cooled to 0℃with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added ]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred overnight at 60 ℃. Water was then added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and was washed with Na 2 SO 4 Dried, filtered and concentrated. The residue was dried under high vacuum. This gives 204mg (purity 40%, 32% of theory) of the target compound.
LC-MS (method 1): rt=1.36 min; MS (ESIpos): m/z=419 [ m+h ]] + 。
Example 25A
rac-3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001022
Under argon, 1- (difluoromethyl) cyclopropyl]Methanol (112 mg, 913. Mu. Mol) was initially added to 5ml DMF and the mixture was cooled to 0℃in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred at 60 ℃. After 6 hours, water was added and extracted with ethyl acetateThe reaction mixture was taken. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was dried under high vacuum. This gives 197mg (purity 51%, 37% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.41min；MS(ESIpos)：m/z＝437[M+H] + 。
Example 26A
rac-3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001031
Under argon, 1- (trifluoromethyl) cyclopropyl]Methanol (128 mg, 913. Mu. Mol) was initially added to 5ml DMF and the mixture was cooled to 0℃with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred at 60 ℃. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was dried under high vacuum. This gives 212mg (purity 58%, 44% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.48min；MS(ESIpos)：m/z＝455[M+H] + 。
Example 27A
3, 3-dimethyl [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001032
Acetic acid (74 μl,1.3 mmol) was added to benzyl 4-oxopiperidine-1-carboxylate (200 mg, 58% purity, 857) Mu mol) and 3, 3-dimethylpiperidine (240. Mu.l, 1.7 mmol) in 7ml dichloromethane, and the mixture was stirred at room temperature for 5h. Subsequently, sodium triacetoxyborohydride (218 mg,1.03 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and saturated NaCl solution and was washed with Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated and the residue is dried under high vacuum. This gives 280mg (purity 81%, 80% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.18min；MS(ESIpos)：m/z＝331[M+H] + 。
Example 28A
4- (5-azaspiro [2.5] oct-5-yl) piperidine-1-carboxylic acid benzyl ester
Figure BDA0004107514540001041
Acetic acid (110. Mu.l, 1.9 mmol) was added to benzyl 4-oxopiperidine-1-carboxylate (300 mg,1.29 mmol) and 5-azaspiro [2.5]]A solution of octane (284 mg,2.57 mmol) in 10ml dichloromethane was added and the mixture was stirred at room temperature for 5h. Subsequently, sodium triacetoxyborohydride (327 mg,1.54 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated and the residue is dried under high vacuum. This gives 368mg (purity 40%, 35% of theory) of the target compound.
LC-MS (method 1): rt=1.12 min; MS (ESIpos): m/z=329 [ m+h ]] + 。
Example 29A
rac-4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidine-1-carboxylic acid benzyl ester
Figure BDA0004107514540001042
Acetic acid (110. Mu.l, 1.9 mmol) was added to benzyl 4-oxopiperidine-1-carboxylate (300 mg,1.29 mmol) and rac-1, 1-difluoro-5-azaspiro [2.5]]Octane hydrochloride (300 mg,1.29 mmol) and rac-1, 1-difluoro-5-azaspiro [2.5]]Octane hydrochloride (354 mg,1.93 mmol) in 10ml dichloromethane and the mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (327 mg,1.54 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off, the filtrate is concentrated on a rotary evaporator and the residue is dried under high vacuum. This gives 405mg (purity 61%, 53% of theory) of the target compound.
LC-MS (method 1): rt=1.14 min; MS (ESIpos): m/z=365 [ m+h ]] + 。
Example 30A
rac-3-hydroxy [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001051
Triethylamine (1.8 ml,13 mmol) and acetic acid (740. Mu.l, 13 mmol) were added to a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g,8.57 mmol) and piperidin-3-ol (1.73 g,17.1 mmol) in 100ml dichloromethane, and the mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (2.18 g,10.3 mmol) was added to the reaction, and the mixture was stirred at room temperature for 48 hours. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. Applying the residue to
Figure BDA0004107514540001053
And passing the mixture throughColumn chromatography (+)>
Figure BDA0004107514540001054
Isolera One; column: snap Ultra50g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 1.87g (purity 100%, 68% of theory) of the target compound.
LC-MS (method 1): rt=0.88 min; MS (ESIpos): m/z=319 [ m+h ]] + 。
Example 31A
rac-3- (cyclopropylmethoxy) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001052
Benzyl 3-hydroxy [1,4 '-bipiperidine ] -1' -carboxylate (250 mg, 785. Mu. Mol) was initially charged to 5ml THF under argon and the mixture was cooled to 0℃with an ice bath. At this temperature, sodium hydride (47.1 mg, purity 60%,1.18 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl) cyclopropane (110 μl,1.2 mmol) was added and the mixture was stirred at 60 ℃ overnight. (bromomethyl) cyclopropane (110. Mu.l, 1.2 mmol) and sodium hydride (47.1 mg, 60% purity, 1.18 mmol) were added and the mixture was stirred at 60℃for an additional 24 hours. Subsequently, the product was isolated by preparative HPLC (column: chromaorex C18 μm,250x30mm, mobile phase A=water, B=acetonitrile; gradient: 0.0min 5%B;3min 5%B;20min 50%B;23min 100%B;26min 5%B; flow rate: 50ml/min;0.1% formic acid). The product-containing fractions were combined and concentrated on a rotary evaporator and the residue was dried under high vacuum. This gives 68.0mg (purity 68%, 16% of theory) of the target compound.
LC-MS (method 1): rt=1.25 min; MS (ESIpos): m/z=373 [ m+h ]] + 。
Example 32A
rac-3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001061
Cyclobutanol (72 μl,910 μmol) was initially added to 5ml dmf under argon and the mixture was cooled to 0 ℃ with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred overnight at 60 ℃. Water was then added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and was washed with Na 2 SO 4 Dried, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gives 290mg (purity 46%, 57% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.73min；MS(ESIpos)：m/z＝387[M+H] + 。
Example 33A
rac-3- [ (cyclopropylmethoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001062
Sodium hydride (268 mg, 60% purity, 6.70 mmol) was initially added to 25ml dmf under argon and the mixture was cooled to 0 ℃ with an ice bath. At this temperature, cyclopropylmethanol (540 μl,6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added ]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (2.50 g,6.09 mmol) and the reaction mixture was stirred overnight at 55 ℃. Cyclopropylmethanol (540 μl,6.7 mmol) and sodium hydride (268 mg, 60% purity, 6.70 mmol) were added and the mixture was stirred at 55deg.C for an additional 24 hours. Water was then added and the reaction mixture was extracted with ethyl acetate. Water is used for the organic phaseAnd saturated NaCl solution, washed with Na 2 SO 4 Dried, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (instrument: waters Prep LC/MS system, column: phenomenex Kinetex C, 5 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% strength formic acid in water, mobile phase D: acetonitrile/water (80% v/20% v), total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete sample injection; gradient profile: mobile phase A0 to 2 min 63ml, mobile phase B0 to 2 min 7ml, mobile phase A2 to 10 min from 63ml to 39ml, mobile phase B from 7ml to 31ml,10 to 12 min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D each are constant flow rates of 5 ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 241mg (purity 78%, 8% of theory) of the target compound.
LC-MS (method 1): rt=1.27 min; MS (ESIpos): m/z=387 [ m+h ]] + 。
Example 34A
4- [ (3R) -3-Methylpiperidin-1-yl ] azepane-1-carboxylic acid tert-butyl ester
Figure BDA0004107514540001071
Acetic acid (72 μl,1.3 mmol) was added to a solution of tert-butyl 4-oxo-azepane-1-carboxylate (178 mg,840 μl) and (3R) -3-methylpiperidine (167 mg,1.68 mmol) in 5ml dichloromethane and the mixture was stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (214 mg,1.01 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Subsequently, saturated NaHCO is added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off with suction, the filtrate is concentrated on a rotary evaporator and the residue is dried under high vacuum. This gave 215mg of a mixture which was further reacted without further purification and analysis.
Example 35A
diamix-3- ({ [ -2, 2-difluorocyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001081
Rac- (2, 2-difluorocyclopropyl) methanol (98.7 mg, 913. Mu. Mol) was initially charged to 5ml DMF under argon, and the mixture was cooled to 0℃with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added ]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 609. Mu. Mol) and the reaction mixture was stirred overnight at 60 ℃. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 Dried, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gives 343mg (purity 56%, 74% of theory) of the target compound.
LC-MS (method 1): rt=1.32 min; MS (ESIpos): m/z=423 [ m+h ]] + 。
Example 36A
rac-3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001082
(3, 3-difluorocyclobutyl) methanol (112 mg, 913. Mu. Mol) was initially charged to 5ml of DMF under argon, and the mixture was cooled to 0℃with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913. Mu. Mol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3- { [ (methylsulfonyl) oxy was added]Methyl } [1,4' -bipiperidine]Benzyl 1' -formate (250 mg, 319 gmol) and the reaction mixture was stirred at 60 ℃. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase is saturated with waterWashing with NaCl solution, passing through Na 2 SO 4 Dried, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gives 287mg (purity 33%, 36% of theory) of the target compound.
LC-MS (method 1): rt=1.44 min; MS (ESIpos): m/z=437 [ m+h ]] + 。
Example 37A
3- (difluoromethyl) -1,4' -bipiperidine dihydrochloride (racemate)
Figure BDA0004107514540001091
1.35g (3.83 mmol) of 3- (difluoromethyl) [1,4' -bipiperidine are reacted]Benzyl-1' -formate (racemate) was dissolved in 100ml of ethanol, and H-Cube (Thales Nano H-Cube Pro) TM -1.7) hydrogenation.
Reaction conditions:
catalyst: pd/C10%; solvent: ethanol; cylinder pressure: 1 bar hydrogen; flow rate: 1 ml/min; temperature: 50 DEG C
After complete conversion, 4N HCl (in dioxane) was added and the reaction mixture was concentrated to dryness. The resulting residue was dried at room temperature under reduced pressure overnight. This gives 1, 107g (3.80 mmol, 99% of theory) of the title compound as a white solid. The target compound was further reacted without further purification.
GC-MS (method 3): r is R t ＝4.87min；m/z＝218(M-2HCl) + 。
Example 38A
3- [ (3, 3-Difluorocyclobutyl) methoxy ] -1,4' -bipiperidine (racemate)
Figure BDA0004107514540001092
2.7g (6.39 mmol) of 3- [ (3, 3-difluorocyclobutyl) methoxy are reacted][1,4' -bipiperidines ]Benzyl-1' -formate (racemate) was dissolved in 90ml of ethanol, andusing H-Cube (Thales Nano H-Cube Pro) TM -1.7) hydrogenation.
Reaction conditions:
catalyst: pd/C10%; solvent: ethanol; cylinder pressure: 50 bar hydrogen; flow rate: 1 ml/min; temperature: 50 DEG C
After the reaction was completed, the reaction mixture was concentrated to dryness. The resulting residue was dried at room temperature under reduced pressure overnight. This gives 1.27g (4.40 mmol, 69% of theory) of the title compound as a yellow oil. The target compound was further reacted without further purification.
GC-MS (method 3): r is R t ＝6.42min；m/z＝288(M) + 。
The following compounds of examples 39A to 4lA were prepared analogously to examples 37A and 38A from the starting materials described in each case.
Figure BDA0004107514540001101
Example 42A
rac-3- (methoxymethyl) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001102
Rac-3- (methoxymethyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (145 mg, 419. Mu. Mol) was initially taken in 5ml THF and palladium (50.0 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (310 μl,2.0m,630 μmol) in diethyl ether was added to the filtrate, and the precipitated solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. This gives 92.0mg (purity 76%, 59% of theory) of the target compound.
GC-MS (method 3): rt=5.45 min; MS (ESIpos): m/z=212 [ m-HCl] + 。
Example 43A
diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride
Figure BDA0004107514540001111
The synthesis method 1 comprises the following steps:
diaminox- (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -carboxylic acid benzyl ester (5.13 g, purity 55%,8.40 mmol) was initially taken in 250ml THF and palladium (382 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (6.3 ml,2.0m,13 mmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane and the solid was filtered off with suction, washed with dichloromethane and dried under high vacuum. This gives 2.31g (100% of theory) of the target compound.
LC-MS (method 4): MS (ESIpos): m/z=200 [ m-2HCl] + 。
The synthesis method 2 comprises the following steps:
4M hydrochloric acid in 1, 4-dioxane (22 ml,4.0M,88 mmol) was added to a solution of diamix- (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -carboxylic acid tert-butyl ester (5.30 g,17.6 mmol) in dichloromethane and the mixture was stirred at room temperature for 48 hours. The precipitated solid was filtered off with suction, washed with dichloromethane and dried overnight at 40 ℃ in a vacuum oven. This gives 3.47g (purity 100%, 72% of theory) of the target compound.
GC-MS (method 3): MS (ESIpos): m/z=200 [ m-2HCl] + 。
Example 44A
rac-3- [ (2, 2-trifluoroethoxy) methyl ] -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001112
Rac-3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (218 mg, purity 81%, 526. Mu. Mol) was initially taken in 12ml THF and palladium (63 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 3.5 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid (390 μl,2.0m,790 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gives 164mg (purity 74%, 66% of theory) of the target compound.
GC-MS (method 3): r is R t ＝5.26min；MS(full ms)：m/z＝280[M-2HCl] + 。
Example 45A
rac-3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001121
Rac-3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (204 mg, purity 40%, 487. Mu. Mol) was initially taken in 10ml THF and palladium (58 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 2 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid (370 μl,2.0m,740 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 133mg of a mixture which was reacted without further purification and analysis.
Example 46A
rac-3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001122
Rac-3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (197 mg, purity 51%, 451. Mu. Mol) was initially taken in 10ml THF and palladium (54 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid (374 μl,2.0m,680 gmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 112mg of a mixture which was reacted without further purification and analysis.
Example 47A
rac-3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001131
Rac-3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (212 mg, 58% purity, 466. Mu. Mol) was initially taken in 10ml THF and palladium (56 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid (350 μl,2.0m,700 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 129mg of a mixture which was reacted further without further purification and analysis.
Example 48A
3, 3-dimethyl-1, 4' -bipiperidine dihydrochloride
Figure BDA0004107514540001132
Benzyl 3, 3-dimethyl [1,4 '-bipiperidine ] [ 1' -carboxylate (260 mg, 81% purity, 637. Mu. Mol) was initially charged in 18ml THF, and palladium (27 mg;10% on charcoal, 255. Mu. Mol) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (478 μl,2.0m,956 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 180mg of a mixture which was reacted further without further purification and analysis.
Example 49A
5- (piperidin-4-yl) -5-azaspiro [2.5] octane dihydrochloride
Figure BDA0004107514540001133
Benzyl 4 (5 x azaspiro [2.5] oct-5-yl) piperidine 1-carboxylate (368 mg, purity 40%,1.12 mmol) was initially charged in 32ml THF and palladium (51 mg, 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (840 μl,2.0m,1.7 mmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane. The precipitated solid was filtered off with suction, washed with dichloromethane and dried under high vacuum. This gave 185mg of a mixture which was reacted further without further purification and analysis.
Example 50A
rac-1, 1-difluoro-5- (piperidin-4-yl) -5-azaspiro [2.5] octane dihydrochloride
Figure BDA0004107514540001141
Rac-4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidine-1-carboxylic acid benzyl ester (405 mg, purity 61%,1.11 mmol) was initially charged to 32ml THF and palladium (51 mg,10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (840 μl,2.0m,1.7 mmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated on a rotary evaporator and dried under high vacuum. This gave 280mg of a mixture which was reacted further without further purification and analysis.
Example 51A
rac-3- (cyclopropylmethoxy) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001142
Rac-3- (cyclopropylmethoxy) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (68.0 mg, purity 68%, 124. Mu. Mol) was initially taken in 5ml THF and palladium (22 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (93 μl,2.0m,186 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 51mg of a mixture which was further reacted without further purification and analysis.
Example 52A
rac-3- [ (cyclobutoxy) methyl ] -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001151
Rac-3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (290 mg, 46% pure, 386. Mu. Mol) was initially taken in 15ml THF and palladium (41 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (259 μl,2.0m,518 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 225mg of a mixture which was further reacted without further purification and analysis.
Example 53A
rac-3- [ (cyclopropylmethoxy) methyl ] -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001152
Rac-3- [ (cyclopropylmethoxy) methyl ] [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (241 mg, 78% pure, 486. Mu. Mol) was initially taken in 20ml THF and palladium (58 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (360 μl,2.0m,730 μmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 155mg of a mixture which was reacted further without further purification and analysis.
Example 54A
4- [ (3R) -3-methylpiperidin-1-yl ] azepane dihydrochloride
Figure BDA0004107514540001153
4M hydrochloric acid in 1, 4-dioxane (2.2 ml,4.0M,8.6 mmol) was added to a solution of tert-butyl 4- [ (3R) -3-methylpiperidin-1-yl ] azepan-1-carboxylate (215 mg) in 5.4ml dichloromethane and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 237mg of a mixture which was reacted further without further purification and analysis.
Example 55A
diamix-3- [ (3-fluorobutoxy) methyl ] -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001161
Diamix-3- ({ [ -2, 2-difluorocyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (343 mg, purity 56%, 446. Mu. Mol) was initially taken in 25ml THF and palladium (53 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (330 μl,2.0m,670 gmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 218mg of a mixture which was further reacted without further purification and analysis.
Example 56A
rac-3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001162
Rac-3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester (287 mg, 33% pure, 217. Mu. Mol) was initially taken in 15ml THF and palladium (26 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (163 μl,2.0m,325 gmol) in diethyl ether was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 286mg of a mixture which was further reacted without further purification and analysis.
Example 57A
2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid methyl ester
Figure BDA0004107514540001171
5g (22.52 mmol) of methyl 2-bromo-1, 3-thiazole-5-carboxylate, 4.926g (22.52 mmol) of 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride and 9.4ml (67.55 mmol) of triethylamine are heated to the boiling point (oil bath temperature. About.100 ℃ C.) in 30ml of 2-propanol and stirred at this temperature overnight. After the reaction mixture was cooled, the solution was concentrated to dryness using a rotary evaporator. This gave 14.29g (crude product, purity. About.34%) of the desired product and triethylamine salt. The mixture was further reacted without further purification.
LC-MS (method 4): r is R t ＝0.51min；m/z＝324(M+H) + 。
Example 58A
2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride
Figure BDA0004107514540001172
A mixture of 14.29g of methyl 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylate and triethylamine salt was dissolved in water, and 221ml of 1N NaOH solution was added. The brown oil was separated off and dissolved by the addition of 50ml of THF. The reaction mixture was then heated to 60 ℃ and stirred at this temperature for 1 hour. After the reaction mixture was cooled to room temperature, the solution was concentrated to dryness on a rotary evaporator, taken up in water and acidified with concentrated hydrochloric acid. The solution was then concentrated to dryness again. This gave 20.54g of an off-white solid which was purified by column chromatography.
Conditions are as follows: the separation was carried out with 1g portions. RP column chromatography C18, 10 μm;125x30mm, acetonitrile/water (+0.05% formic acid) 5/95→gradient 20 min→acetonitrile/water (+0.05% formic acid) 95/5, flow rate 75ml/min.
Finally, the product-containing fractions are combined and concentrated to dryness under reduced pressure and dried. This gives 4.75g (12.42 mmol, 83% of theory) of the title compound as a pale beige solid.
LC-MS (method 1): r is R t ＝0.54min；m/z＝310(M+H-2HCl) + 。
Example 59A
3- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1,2, 4-oxadiazole-5-carboxylic acid
Figure BDA0004107514540001181
3-bromo-1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester (100 mg, 452. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (173 mg, 679. Mu. Mol) were stirred in 2ml of sodium carbonate solution (2.0 ml,2.0M,4.0 mmol) at 120 ℃. After 30 min, the reaction mixture was acidified with 2N hydrochloric acid and purified by preparative HPLC (column: chromaorex C1810 μm,250x 30mm, mobile phase A=water, B=acetonitrile; gradient: 0.0min 5%B;3min 5%B;20min 50%B:23 min 100% B;26 min 5% B; flow rate: 50ml/min;0.1% formic acid). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 25mg (purity 60%, 11% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.47min；MS(ESIpos)：m/z＝295[M+H] + 。
Example 60A
rac-3- [ (2, 2-difluorocyclopropyl) methoxy ] pyridine hydrochloride
Figure BDA0004107514540001182
Triphenylphosphine (2.43 g,9.25 mmol) was added to a solution of pyridin-3-ol (677 mg,7.12 mmol) in 25ml THF and the mixture was cooled to 0 ℃ in an ice bath. At this temperature diisopropyl azodicarboxylate (1.3 ml,9.3 mmol) was added and the mixture was stirred at 0℃for 5 min. Subsequently, a solution of rac-2, 2-difluorocyclopropylmethanol (1.00 g,9.25 mmol) in 5ml THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, over Na 2 SO 4 Dried, filtered and concentrated. The oily residue was stirred with 75ml cyclohexane for 30 minutes. The precipitated solid was filtered off and the filtrate was concentrated to give a residue. The residue was dissolved in 50ml of MTBE and 5ml of hydrochloric acid (4N in 1, 4-dioxane) was added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This produced 698mg [ ]Purity 93%, 41% of theory).
LC-MS (method 4): r is R t ＝0.40min；MS(ESIpos)：m/z＝186[M-HCl] + 。
Example 61A
diamix-3- [ (2, 2-difluorocyclopropyl) methoxy ] piperidine sulfate hydrochloride
Figure BDA0004107514540001191
Rac-3- [ (2, 2-difluorocyclopropyl) methoxy ] pyridine hydrochloride (698 mg, 93% purity, 2.93 mmol) was dissolved in 35ml ethanol under argon. Sulfuric acid (168. Mu.l, 3.15 mmol) and platinum (IV) oxide (178 mg,0.79 mmol) were added and the mixture was hydrogenated overnight under hydrogen atmosphere. The catalyst was filtered off through celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gives 761mg (74% of theory) of the target compound.
LC-MS (method 5): MS (ESIpos): m/z=192 [ m-HCl-H 2 SO 4 ] + 。
Example 62A
3- (Cyclobutoxy) pyridine hydrochloride
Figure BDA0004107514540001192
Triphenylphosphine (7.17 g,27.3 mmol) was added to a solution of pyridin-3-ol (2.00 g,21.0 mmol) in 70ml THF and the mixture was cooled to 0 ℃ in an ice bath. At this temperature diisopropyl azodicarboxylate (3.9 ml,27 mmol) was added and the mixture was stirred at 0℃for 5 min. Subsequently, a solution of cyclobutylalcohol (2.1 ml,27 mmol) in 10ml THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature for the whole weekend. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, over Na 2 SO 4 Drying, filtering andconcentrating. The oily residue was stirred with 150ml cyclohexane for 30 minutes. The solid was filtered off and the filtrate was concentrated to give a residue. The residue was dissolved in 100ml MTBE and 5ml hydrochloric acid (4N in 1, 4-dioxane) was added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gives 2.02g (purity 51%, 26% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.34min；MS(ESIpos)：m/z＝150[M-HCl] + .
Example 63A
rac-3- (cyclobutoxy) piperidine sulfate hydrochloride
Figure BDA0004107514540001201
3- (Cyclobutoxy) pyridine hydrochloride (2.0 g, 51% purity, 5.51 mmol) was dissolved in 95ml ethanol under argon. Sulfuric acid (550. Mu.l, 10 mmol) and platinum (IV) oxide (612 mg,2.6 mmol) were added, and the mixture was hydrogenated overnight under hydrogen atmosphere. The catalyst was filtered off through celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gives 2.52g (157% of theory) of the target compound.
LC/MS (method 4): MS (ESIpos): m/z=156 [ m-HCl-H 2 SO 4 ] + 。
Example 64A
3- [ (3, 3-difluorocyclobutyl) oxy ] pyridine hydrochloride
Figure BDA0004107514540001202
Triphenylphosphine (2.43 g,9.25 mmol) was added to a solution of pyridin-3-ol (677 mg,7.12 mmol) in 25ml THF and the mixture was cooled to 0 ℃ in an ice bath. At this temperature diisopropyl azodicarboxylate (1.3 ml,9.3 mmol) was added and the mixture was stirred at 0℃for 5 min. Subsequently, 3-difluorocyclobutanol (1.00 g,9.25m mol) in 5ml THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature overnight. The reaction mixture was stirred at 80 ℃ for 5 hours, then extracted between water and ethyl acetate. The organic phase was washed with saturated NaCl solution, over Na 2 SO 4 Dried, filtered and concentrated. The oily residue was stirred with 150ml cyclohexane for 30 minutes. The precipitated solid was filtered off and the filtrate was concentrated to give a residue. The residue was dissolved in 100ml MTBE and 5ml hydrochloric acid (4N in 1, 4-dioxane) was added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gives 289mg (purity 94%, 17% of theory) of the target compound.
LC-MS (method 4): r is R t ＝1.01min；MS(ESIpos)：m/z＝186[M-HCl] + 。
Example 65A
rac-3- [ (3, 3-difluorocyclobutyl) oxy ] piperidine sulfate hydrochloride
Figure BDA0004107514540001211
3- [ (3, 3-difluorocyclobutyl) oxy ] pyridine hydrochloride (298 mg,1.34 mmol) was dissolved in 12ml of ethanol under argon. Sulfuric acid (72. Mu.l, 1.3 mmol) and platinum (IV) oxide (76.3 mg, 336. Mu. Mol) were added, and the mixture was hydrogenated under a hydrogen atmosphere for 3 hours. The catalyst was filtered off through celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gives 297mg (68% of theory) of the target compound.
LC/MS (method 4): MS (ESIpos): m/z=192 [ m-HCl-H 2 SO 4 ] + 。
Example 66A
2-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-oxazole-4-carboxamide
Figure BDA0004107514540001212
N, N-diisopropylethylamine (680 μl,3.9 mmol) and propylphosphonic anhydride (1.0 ml,50% in ethyl acetate, 1.7 mmol) were added to a solution of 2-bromo-1, 3-oxazole-4-carboxylic acid (250 mg,1.30 mmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (283 mg,1.30 mmol) in 10ml acetonitrile and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. Applying the residue to
Figure BDA0004107514540001213
And purifying the mixture by column chromatography (++>
Figure BDA0004107514540001214
Isolera One; column: snap Ultra 10g; cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 193mg (46% of theory, 84% purity) of the target compound which is reacted further without further purification.
LC-MS (method 1): r is R t ＝1.32min；MS(ESIpos)：m/z＝274[M+H] + 。
Example 67A
2-bromo-N- (5-chloro-2-fluorobenzyl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001221
N, N-diisopropylethylamine (630 μl,3.6 mmol) and propylphosphonic anhydride (930 μl,50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1, 3-thiazole-5-carboxylic acid (250 mg,1.20 mmol) and 1- (5-chloro-2-fluorophenyl) methylamine (192 mg,1.20 mmol) in 10ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate and taken up in saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. Applying the residue to
Figure BDA0004107514540001222
And purifying the mixture by column chromatography (++>
Figure BDA0004107514540001223
Isolera One; column: snap Ultra 10g; cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 106mg (purity 96%, 24% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.85min；MS(ESIpos)：m/z＝348[M+H] + 。
Example 68A
(3R) -3-hydroxy [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001224
Triethylamine (3.0 ml,21 mmol) and acetic acid (740. Mu.l, 13 mmol) were added to a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g,8.57 mmol) and (3R) -piperidine-3-alkoxide (2.36 g,17.1 mmol) in 100ml dichloromethane, and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (2.18 g,10.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 48 hours. Adding saturated NaHCO 3 The solution was extracted with dichloromethane. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. Applying the residue to
Figure BDA0004107514540001225
And subjecting the mixture to column chromatography (+.>
Figure BDA0004107514540001226
Isolera One; column: snap Ultra 50g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 1.79g (purity 100%, 66% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.87min；MS(ESIpos)：m/z＝319[M+H] + 。
Example 69A
(3R) -3- (cyclopropylmethoxy) [1,4 '-bipiperidine ] -1' -carboxylic acid benzyl ester
Figure BDA0004107514540001231
Under argon, the (3R) -3-hydroxy [1,4' -bipiperidine]Benzyl-1' -formate (1.79 g,5.62 mmol) was initially taken in 40ml THF and the mixture was cooled to 0℃with an ice-bath. At this temperature, sodium hydride (337 mg, purity 60%,8.43 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl) cyclopropane (820 μl,8.4 mmol) was added and the reaction mixture was stirred at 60 ℃ overnight. (bromomethyl) cyclopropane (820 μl,8.4 mmol) and sodium hydride (337 mg, purity 60%,8.43 mmol) were added, and the mixture was stirred at 60 ℃ for an additional 24 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and was washed with Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The product was purified by preparative HPLC (instrument: waters Prep LC/MS system, column: phenomenex Kinetex C18 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% strength formic acid in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete sample injection. Gradient plot: mobile phase A0 to 2 min 63ml, mobile phase B0 to 2 min 7ml, mobile phase A2 to 10 min from 63ml to 39ml, mobile phase B from 7ml to 31ml,10 to 12 min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were constant flow rates of 5 ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 100.0mg (purity 100%, 4.8% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.19min；MS(ESIpos)：m/z＝373[M+H] + 。
Example 70A
(3R) -3- (cyclopropylmethoxy) -1,4' -bipiperidine dihydrochloride
Figure BDA0004107514540001241
Benzyl (3R) -3- (cyclopropylmethoxy) [1,4 '-bipiperidine ] -1' -carboxylate (100 mg, 268. Mu. Mol) was initially taken in 7.5ml THF, and palladium (32.1 mg;10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere for 2 hours. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid (200. Mu.l, 2.0M, 400. Mu. Mol) in diethyl ether was added to the filtrate, and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 66mg of a mixture which was further reacted without further purification and analysis.
Example 71A
rac-2-bromo-N- [1- (2, 5-difluorophenyl) ethyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001242
N, N-diisopropylethylamine (630 μl,3.6 mmol) and propylphosphonic anhydride (930 μl,50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1, 3-thiazole-5-carboxylic acid (250 mg,1.20 mmol) and rac-1- (2, 5-difluorophenyl) ethylamine (189 mg,1.20 mmol) in 10ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na2SO 4 And (5) drying. Filtering outDrying agent, and concentrating the filtrate. Applying the residue to
Figure BDA0004107514540001243
And purifying the mixture by column chromatography (++>
Figure BDA0004107514540001244
Isolera One; column: snap Ultra 10g; cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 148mg (purity 100%, 35% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.81min；MS(ESIpos)：m/z＝346[M+H] + 。
Example 72A
4- (2-chlorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid ethyl ester
Figure BDA0004107514540001251
Ethyl 2-bromo-4- (2-chlorophenyl) -1, 3-thiazole-5-carboxylate (150 mg, 433. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (166 mg, 649. Mu. Mol) were combined and stirred in sodium carbonate solution (870. Mu.l, 2.0M,1.7 mmol) at 120℃for 30 minutes. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dried under high vacuum. This gives 199mg (purity 95%, 98% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.34min；MS(ESIpos)：m/z＝449[M+H] + 。
Example 82A
diamix-5- (3-fluoropiperidin-4-yl) -5-azaspiro [2.5] octane dihydrochloride
Figure BDA0004107514540001252
4M hydrochloric acid (720 μl,4.0M,2.9 mmol) in 1, 4-dioxane was added to a solution of diamix-4- (5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (178 mg,573 μmol) in 8ml dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 162mg of a mixture which was further reacted without further purification and analysis.
Example 73A
4- (2-chlorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid
Figure BDA0004107514540001253
4- (2-chlorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid ethyl ester (199mg, 444. Mu. Mol) was dissolved in 10ml THF. Aqueous sodium hydroxide (4 ml,2.0m,8 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 days. THF was removed on a rotary evaporator and the residue was acidified with hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gives 160mg (purity 98%, 84% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.97min；MS(ESIpos)：m/z＝420[M+H] + 。
Example 74A
4-bromo-2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid
Figure BDA0004107514540001261
2, 4-dibromo-1, 3-thiazole-5-carboxylic acid (150 mg, 523. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (133 mg, 523. Mu. Mol) were combined and stirred in sodium carbonate solution (1.0 ml,2.0M,2.1 mmol) at 120℃for 1 hour. Subsequently, the reaction mixture was concentrated to dryness and purified with DCM/MeOH 5:1 are stirred together. The insoluble salts were filtered off with suction. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gives 240mg (purity 100%, 118% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.70min；MS(ESIpos)：m/z＝388[M+H] + 。
Example 75A
2-bromo-4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001262
N, N-diisopropylethylamine (720 μl,4.1 mmol) and propylphosphonic anhydride (800 μl,50% in ethyl acetate, 1.3 mmol) were added to a solution of 2-bromo-4-chloro-1, 3-thiazole-5-carboxylic acid (250 mg,1.03 mmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (2910 mg,1.34 mmol) in 14ml acetonitrile, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dried under high vacuum. This gives 250mg (purity 95%, 62% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.79min；MS(ESIpos)：m/z＝367[M+H] + 。
Example 76A
2-bromo-4-cyclopropyl-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001271
N, N-diisopropylethylamine (560 μl,3.2 mmol) and propylphosphonic anhydride (620 μl, 50%)In ethyl acetate, 1.0 mmol) was added to a solution of 2-bromo-4-cyclopropyl-1, 3-thiazole-5-carboxylic acid (200 mg,806 μmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (227 mg,1.05 mmol) in 11ml acetonitrile and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dried under high vacuum. This gives 239mg (purity 78%, 62% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.87min；MS(ESIpos)：m/z＝373[M+H] + 。
Example 77A
2-bromo-4-ethyl-1, 3-thiazole-5-carboxylic acid
Figure BDA0004107514540001272
2-bromo-4-ethyl-1, 3-thiazole-5-carboxylic acid methyl ester (150 mg, 600. Mu. Mol) was dissolved in 3ml THF. Aqueous sodium hydroxide (3 ml,2.0m,6 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. THF was removed on a rotary evaporator and the residue was acidified with 2N hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gives 100mg (purity 98%, 69% of theory) of the target compound.
LC-MS (method 1): rt=1.30 min; MS (ESIpos): m/z=235 [ m+h ]] + 。
Example 78A
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-ethyl-1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001281
N, N-diisopropylethylamine (300 μl,1.7 mmol) and propylphosphonic anhydride (330 μl,50% in ethyl acetate,550. Mu. Mol) was added to a solution of 2-bromo-4-ethyl-1, 3-thiazole-5-carboxylic acid (100 mg, 424. Mu. Mol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (120 mg, 550. Mu. Mol) in 5.7ml of acetonitrile, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution, water and saturated NaCl solution were washed. The organic phase was taken up in Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dried under high vacuum. This gives 150mg (purity 95%, 93% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.86min；MS(ESIpos)：m/z＝364[M+H] + 。
Example 79A
diamix-4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0004107514540001282
N, N-diisopropylethylamine (570 μl,3.3 mmol) was added to rac-1, 1-difluoro-5-azaspiro [2.5]]To a solution of octane hydrochloride (600 mg,3.27 mmol) in 15ml1, 2-dichloroethane, and the mixture was stirred for 5 minutes, then rac-3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (355 mg,1.63 mmol) and acetic acid (140 μl,2.5 mmol) were added. The mixture was then stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg,1.96 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: waters Prep LC/MS system, column: phenomenex Kinetex C5 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete)And (5) sample injection. Gradient curve: mobile phase A0 to 2 min 70ml, mobile phase B0 to 2 min 0ml, mobile phase A2 to 10 min 70ml to 55ml, mobile phase B0 ml to 15ml,10 to 12 min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 264mg (purity 100%, 46% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.56min；MS(ESIpos)：m/z＝349[M+H] + 。
Example 80A
diamix-1, 1-difluoro-5- (3-fluoropiperidin-4-yl) -5-azaspiro [2.5] octane dihydrochloride
Figure BDA0004107514540001291
4M hydrochloric acid in 1, 4-dioxane (950 μl,4.0M,3.8 mmol) was added to a solution of diamix-4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (264 mg,760 μmol) in 10ml dichloromethane and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 246mg of a mixture which was reacted further without further purification and analysis.
Example 81A
diamix-4- (5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0004107514540001292
N, N-diisopropylethylamine (410 μl,2.4 mmol) was added to 5-azaspiro [2.5]]Octane hydrochloride (350 mg,2.37 mmol) in 10ml dichloroethane and the mixture was stirred for 5 min before adding rac-3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (257 mg,1.19 mmol) to the mixtureAnd acetic acid (100. Mu.l, 1.8 mmol). The mixture was then stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg,1.96 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: waters Prep LC/MS system, column: phenomenex Kinetex C5 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% strength formic acid in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete sample injection. Gradient profile: mobile phase A0 to 2 min 70ml, mobile phase B0 to 2 min 0ml, mobile phase A2 to 10 min 70ml to 55ml, mobile phase B0 ml to 15ml,10 to 12 min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5 ml/min each over the whole run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 179mg (purity 100%, 48% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.53min；MS(ESIpos)：m/z＝313[M+H] + 。
Example 82A
5- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1,3, 4-thiadiazole-2-carboxylic acid ethyl ester
Figure BDA0004107514540001301
3.67ml (21.09 mmol) of N, N-diisopropylethylamine were added to 1g (4.22 mmol) of ethyl 5-bromo-1, 3, 4-thiadiazole-2-carboxylate and 1.077g (4.22 mmol) of 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride in 25ml of acetonitrile and the mixture was heated to 80℃and stirred at this temperature overnight. After the reaction mixture was cooled, the solution was diluted with ethyl acetate and washed with water. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. This gives 1.29g (3.81 mmol, 90% of theory) of the title compound as a red solid.
1 H NMR(600MHz，DMSO-d 6 )δ[ppm]:0.77-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.30 (t, 3H), 1.34-1.46 (m, 1H), 1.48-1.67 (m, 5H), 1.72-1.85 (m, 3H), 2.06 (br.t, 1H), 2.48-2.58 (m, 1H, partially masked by DMSO), 2.74 (br.t, 2H), 3.24 (td, 2H), 3.98 (br.d, 2H), 4.34 (q, 2H).
LC-MS (method 1): r is R t ＝0.82min；m/z＝339(M+H) + 。
Example 83A
5- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1,3, 4-thiadiazole-2-carboxylic acid
Figure BDA0004107514540001302
1.52g (4.49 mmol) of ethyl 5- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1,3, 4-thiadiazole-2-carboxylate are dissolved in 8ml of THF, 538mg (22.45 mmol) of lithium hydroxide are added, and then 5ml of water are added to the reaction solution. The reaction solution was then stirred at room temperature for several hours. After complete conversion, the reaction solution was adjusted to pH 7 with 1N hydrochloric acid and concentrated to dryness on a rotary evaporator. This gave 2.95g of an amber oil, which was purified by column chromatography.
Conditions are as follows: about 1g of the fraction was used for separation. RP column chromatography C18, 10 μm;125x30mm, acetonitrile/water 10/90→gradient 38 min→acetonitrile/water 90/10 flow rate 75ml/min.
Finally, the product-containing fractions are combined and concentrated to dryness under reduced pressure and dried. This gives 487mg (1.57 mmol, 35% of theory) of the title compound as a white solid.
LC-MS (method 1): r is R t ＝0.39min；m/z＝311(M+H) + 。
Working examples:
example 1
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001311
13g (38.91 mmol) of 2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 8.51g (38.91 mmol) of (3R) -3-methyl-1, 4' -bipiperidine hydrochloride (1:1) (CAS registry number 1799475-27-6) and 20.62g (194.53 mmol) of sodium carbonate are heated to 120℃in 200ml of water and stirred at this temperature overnight. After the reaction mixture was cooled, the solution was extracted with ethyl acetate. The separated organic phase was then filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The resulting residue was taken up in acetonitrile, heated to 80 ℃ and cooled slowly back to room temperature with stirring. The precipitated solid was filtered off with suction and washed with acetonitrile. The residue was then again taken up in acetonitrile and recrystallized again. This gives 10.75g (24.68 mmol, 63% of theory) of the title compound as a pale beige solid. The two mother liquors were combined and concentrated to dryness on a rotary evaporator. The residue obtained is further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100g column mobile phase: dichloromethane→gradient 20CV (cv=column volume) →dichloromethane/methanol 9:1). The resulting product fractions were then combined, concentrated on a rotary evaporator and recrystallized from acetonitrile. This gives an additional 3.28g (7.48 mmol, 19% of theory) of the title compound as a pale beige solid.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.76-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.66 (m, 6H), 1.71-1.81 (m, 3H), 2.01-2.09 (m, 1H), 2.44-2.56 (m, 1H, partially masked by DMSO), 2.69-2.77 (m, 2H), 3.04 (td, 2H), 3.93 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (s, 1H), 7.88-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).
LC-MS (method 4): r is R t ＝0.50min；m/z＝436(M+H) + 。
[α] D 20 -8.06 ° (c=0.430, methanol).
Example 2
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001321
60mg (0.18 mmol) of 2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 51mg (0.18 mmol) of 2- (piperidin-4-yl) -1,2,3, 4-tetrahydroisoquinoline dihydrochloride and 95mg (0.9 mmol) of sodium carbonate are heated in 1ml of water in a closed vessel to 160℃and stirred at this temperature for 30 minutes. After the reaction mixture was cooled, water was added, and the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The residue obtained is further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10g column mobile phase: ethyl acetate→gradient 5CV (cv=column volume) →ethyl acetate/methanol 95:5). The resulting product fractions were then combined and concentrated to dryness on a rotary evaporator. This gives 62.7mg (0.13 mmol, 74% of theory) of the title compound as a yellow solid.
1 H-NMR(600MHz，DMSO-d 6 ，δ/ppm)：1.55-1.65(m，2H)，1.86-1.94(m，2H)，2.67-2.73(m，1H)，2.73-2.81(m，4H)，3.12(br.t，2H)，3.70(S，2H)，3.97(br.d，2H)，4.53(br.d，2H)，7.01-7.12(m，4H)，7.85(s，1H)，7.93(td，1H)，8.48(d，1H)，8.76(t，1H)。
LC-MS (method 1): r is R t ＝0.97min；m/z＝470(M+H) + 。
Example 3
2- [3- (cyclopropylmethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (racemate)
Figure BDA0004107514540001331
32mg (0.10 mmol) of 2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, 22mg (0.10 mmol) of 3- (cyclopropylmethyl) -1,4' -bipiperidine (racemate) and 31mg (0.29 mmol) of sodium carbonate are heated to 120℃in 1ml of water in a closed vessel and stirred at this temperature for 30 minutes. After the reaction mixture was cooled, the solution was extracted with dichloromethane. The separated organic phase WAs then filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, d=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The resulting residue was purified by the following method.
Method 7: instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 40.8mg (0.09 mmol, 88% of theory) of the target compound in the form of a white lyophilizate.
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): -0.07-0.03 (m, 2H), 0.34-0.43 (m, 2H), 0.60-0.73 (m, 1H), 0.80-0.94 (m, 1H), 0.99-1.14 (m, 2H), 1.32-1.65 (m, 5H), 1.68-1.91 (m, 4H), 2.02-2.14 (m, 1H), 2.44-2.59 (m, 1H, partially masked by DMSO), 2.73 (br.d, 1H), 2.83 (br.d, 1H), 3.04 (br.t, 2H), 3.94 (br.d, 2H), 4.52 (br.d, 2H), 7.83 (s, 1H), 7.87-7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).
LC-MS (method 1): r is R t ＝1.13min；m/z＝476(M+H) + 。
Analogously to examples 1 to 3, prepared from the starting materials described in each caseExamples 4 to 14The following compounds:
Figure BDA0004107514540001341
Figure BDA0004107514540001351
Figure BDA0004107514540001361
Figure BDA0004107514540001371
Figure BDA0004107514540001381
Figure BDA0004107514540001391
Figure BDA0004107514540001401
example 15
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methoxy [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001402
100mg (0.28 mmol) of N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide are dissolved in 5ml of dichloromethane and 65mg (0.57 mmol) of (3R) -3-methoxypiperidine and 24. Mu.l (0.43 mmol) of glacial acetic acid are added. 72mg (0.34 mmol) of sodium acetoxyborohydride are then metered in and the reaction solution is stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN616WA1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 8:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 63ml, mobile phase B0 to 2min 7ml, mobile phase A2 to 10min from 63ml to 39ml and mobile phase B from 7ml to 31ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 62mg (0.14 mmol, 48% of theory) of the target compound as a white lyophilizate.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 1.00-1.11 (m, 1H), 1.30-1.40 (m, 1H), 1.43-1.54 (m, 2H), 1.59-1.66 (m, 1H), 1.77 (br.d, 2H), 1.86-1.93 (m, 1H), 1.98 (t, 1H), 2.11 (t, 1H), 2.47-2.58 (m, 1H, partially masked by DMSO), 2.64 (br.d, IH), 2.94 (br.d, IH), 3.04 (br.t, 2H), 3.12-3.19 (m, 1H), 3.23 (s, 3H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (s, 1H), 7.91 (td, 1H), 8.47 (d, 1H), 8.71 (t, 1H).
LC-MS (method 1): r is R t ＝0.83min；m/z＝452(M+H) + 。
Example 16
2- [3- (difluoromethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (racemate)
Figure BDA0004107514540001411
100mg (0.28 mmol) of N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide are dissolved in 5ml of dichloromethane and 86mg (0.57 mmol) of 3- (difluoromethoxy) piperidine (racemate) and 24. Mu.l (0.43 mmol) of glacial acetic acid are added. 72mg (0.34 mmol) of sodium acetoxyborohydride are then metered in and the reaction solution is stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 9:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 60mg (0.12 mmol, 44% of theory) of the target compound as a white lyophilizate.
1 H-NMR(600MHz，DMSO-d 6 ，δ/ppm)：1.27-1.36(m，1H)，1.36-1.53(m，3H)，1.62-1.69(m，1H)，1.73-1.81(m，2H)，1.85-1.93(m，1H)，2.13-2.25(m，2H)，2.54-2.67(m，2H)，2.90(br.d，1H)，3.05(br.t，2H)，3.94(br.d，2H)，4.01-4.08(m，1H)，4.53(d，2H)，6.57-6.88(m，1H)，7.83(s，1H)，7.91(t，1H)，8.47(d，1H)，8.72(t，1H)。
LC-MS (method 1): r is R t ＝0.91min；m/z＝488(M+H) + 。
Example 17
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-ethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide (racemate)
Figure BDA0004107514540001421
100mg (0.28 mmol) of N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide are dissolved in 5ml of dichloromethane and 64mg (0.57 mmol) of 3-ethylpiperidine (racemate) and 24. Mu.l (0.43 mmol) of glacial acetic acid are added. 72mg (0.34 mmol) of sodium acetoxyborohydride are then metered in and the reaction solution is stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 7:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 46mg (0.10 mmol, 36% of theory) of the target compound as a white lyophilizate.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.76-0.87 (m, 4H, including at 0.85 (t, 3H)), 1.09-1.25 (m, 2H), 1.26-1.34 (m, 1H), 1.34-1.43 (m, 1H), 1.44-1.53 (m, 2H), 1.55-1.62 (m, 1H), 1.65-1.71 (m, 1H), 1.73-1.83 (m, 3H), 2.08 (br.t1H), 2.46-2.56 (m, 1H, partially masked by DMSO), 2.70-2.79 (m, 2H), 3.04 (br.t, 2H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 7.82 (s, 1H), 7.89 (br.t, 1H), 8.46 (d, 1H), 8.67 (t, 1H).
LC-MS (method 1): r is R t ＝0.99min；m/z＝450(M+H) + 。
Example 18
2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- { [4- (trifluoromethyl) pyridin-2-yl ] methyl } -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001431
0.46ml (2.62 mmol) of N, N-diisopropylethylamine was added to 200mg (0.52 mmol) of 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride and 122mg (0.58 mmol) of 1- [4- (trifluoromethyl) pyridin-2-yl ] methylamine hydrochloride (1:1) in 20ml of acetonitrile, and then 0.34ml (0.58 mmol) of a 50% strength solution of T3P (2, 4, 6-tripropyl-1,3,5,2,4,6-trioxotriphosphohexane 2,4, 6-trioxide) in ethyl acetate was added dropwise to the reaction solution at room temperature. After the addition was completed, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 7:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 55mg (0.12 mmol, 23% of theory) of the target compound as a white lyophilizate.
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): 0.74-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.68 (m, 6H), 1.70-1.84 (m, 3H), 1.99-2.11 (m, 1H), 2.44-2.58 (m, 1H, partially masked by DMSO), 2.69-2.80 (m, 2H), 3.06 (td, 2H), 3.95 (br.d, 2H), 4.59 (d, 2H), 7.62 (s, 1H), 7.67 (d, 1H), 7.87 (s, 1H), 8.81 (d, 1H), 8.89 (t, 1H).
LC-MS (method 1): r is R t ＝1.05min；m/z＝469(M+H) + 。
Example 19
2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [3- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001441
100mg (0.26 mmol) of 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride are dissolved in 10ml of dichloromethane, 56mg (0.42 mmol) of 1-chloro-N, N, 2-trimethylprop-1-en-amine are added and the mixture is stirred at room temperature for 30 minutes. Subsequently, 60. Mu.l of pyridine and then 46mg (0.26 mmol) of 1- [3- (trifluoromethyl) phenyl ] methylamine were metered into the reaction solution, and the mixture was stirred at room temperature overnight. After addition of water, the precipitate obtained is filtered off with suction. The resulting biphasic filtrate was separated and the resulting organic phase was filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 11:
instrument: abimed Gilson 305; column: reprosil C1810 μm,250mm x 30mm; mobile phase: water, mobile phase B: acetonitrile; gradient: 0-3min 10% B,3-27min 10% B.fwdarw.95% B,27-34.5min 95%B,34.5-35.5min 95% B.fwdarw.10% B,35.5-36.5min10% B; flow rate: 50ml/min; room temperature; UV detection: 210nm.
This gives 45mg (0.10 mmol, 37% of theory) of the target compound.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.78-0.91 (m, 4H, including at 0.83 (d, 3H)), 1.37-1.69 (m, 6H), 1.73-1.94 (m, 3H), 2.05-2.23 (m, 1H), 2.56-2.67 (m, 1H), 2.73-2.90 (m, 2H), 3.06 (br.t, 2H), 3.96 (br.d, 2H), 4.48 (d, 2H), 7.54-7.65 (m, 4H), 7.84 (s, 1H), 8.84 (t, 1H).
LC-MS (method 1): rt=1.31 min; m/z=467 (m+h) + 。
Example 20
N- [ (3-fluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001451
0.18ml (1.05 mmol) of N, N-diisopropylethylamine are added to 100mg (0.26 mmol) of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride and 47mg (0.29 mmol) of 1- (3-fluoropyridin-2-yl) methylamine hydrochloride (1:1) in10 ml of acetonitrile, and then a solution of 0.17ml (0.29 mmol) of 50% strength T3P (2, 4, 6-tripropyl-1,3,5,2,4,6-trioxytriphosphohexane 2,4, 6-trioxide) in ethyl acetate is metered into the reaction solution at room temperature. After the addition was completed, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616wa 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 9:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 5.4mg (0.01 mmol, 5% of theory) of the target compound as a white lyophilizate.
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): 0.75-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.33-1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.05 (br.t, 1H), 2.44-2.58 (m, 1H, partially masked by DMSO), 2.69-2.80 (m, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.56 (dd, 2H), 7.36-7.43 (m, 1H), 7.64-7.72 (m, 1H), 7.84 (s, 1H), 8.38 (dt, 1H), 8.69 (t, 1H).
LC-MS (method 4): rt=0.48 min; m/z=418 (m+h) + 。
Example 21
N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001461
0.18ml (1.05 mmol) of N, N-diisopropylethylamine are added to a solution of 100mg (0.26 mmol) of 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride and 46mg (0.29 mmol) of 1- (5-chloro-2-fluorophenyl) methylamine in 10ml of acetonitrile, and then 0.17ml (0.29 mmol) of 50% strength T3P (2, 4, 6-tripropyl-1,3,5,2,4,6-trioxytriphosphohexane 2,4, 6-trioxide) in ethyl acetate are metered into the reaction solution at room temperature. After the addition was completed, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
Method 7:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gave 45mg of a mixture which was further purified by column chromatography on silica gel (Isolera Biotagetes SNAP-Ultra10g column; mobile phase: cyclohexane/ethyl acetate 8:2→gradient 15CV (CV=column volume) →cyclohexane/ethyl acetate 2:8). This gives 16mg (0.04 mmol, 14% of theory) of the title compound as a beige solid.
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35-1.67 (m, 6H), 1.72-1.82 (m, 3H), 2.05 (br.t, 1H), 2.45-2.57 (m, 1H, partially masked by DMSO), 2.74 (br.t, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.41 (d, 2H), 7.26 (t, 1H), 7.33-7.40 (m, 2H), 7.85 (s, 1H),8.76(t，1H)。
LC-MS (method 4): r is R t ＝0.68min；m/z＝451/453(M+H) + 。
Example 22
2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -N- [4- (trifluoromethyl) benzyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001471
0.22ml (1.23 mmol) of N, N-diisopropylethylamine was added to 200mg (0.31 mmol, 59% purity) of 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride and 59mg (0.34 mmol) of 1- [4- (trifluoromethyl) phenyl ] methylamine in 10ml of acetonitrile, and then 0.2ml (0.34 mmol) of a 50% strength solution of T3P (2, 4, 6-tripropyl-1,3,5,2,4,6-trioxotriphosphohexane 2,4, 6-trioxide) in ethyl acetate was metered into the reaction solution at room temperature. After the addition was completed, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. Finally, the organic phase is separated off, and the resulting organic solution is filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, d=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.
The method 10 comprises the following steps:
instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm
Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min, room temperature, wavelength 200-400nm, column head sample injection (complete sample injection)
Gradient curve: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min 39ml to 15ml and mobile phase B31 ml to 55ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml/min throughout the run time.
This gives 25mg (0.05 mmol, 17% of theory) of the target compound as a white lyophilizate.
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): 0.74-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.33-1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.00-2.10 (m, 1H), 2.45-2.57 (m, 1H, partially masked by DMSO), 2.70-2.79 (m, 2H), 3.06 (td, 2H), 3.94 (br.d, 2H), 4.47 (d, 2H), 7.50 (d, 2H), 7.70 (d, 2H), 7.84 (s, 1H), 8.83 (t, 1H).
LC-MS (method 1): r is R t ＝1.27min；m/z＝467(M+H) + 。
Analogously to examples 18 to 22, prepared from the starting materials described in each caseExamples 23 to 37The following compounds:
Figure BDA0004107514540001481
Figure BDA0004107514540001491
Figure BDA0004107514540001501
Figure BDA0004107514540001511
Figure BDA0004107514540001521
Figure BDA0004107514540001531
Figure BDA0004107514540001541
Figure BDA0004107514540001551
Example 38 and example 39
2- [3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomers 1 and 2)
Figure BDA0004107514540001561
203mg (0.43 mmol) of racemic 2- [3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (example 4) are separated into the enantiomers on the chiral phase by preparative HPLC [ column: daicel Chiralpak AY-H,5 μm,250 mm. Times.20 mm; mobile phase: 2-propanol +0.2% diethylamine/n-heptane 50:50; flow rate: 20ml/min; UV detection: 220nm; temperature: 40 ℃ ]:
example 38 (enantiomer 1):
2- [ (3S) -3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001562
Yield: 97mg of
Rt=4.93 min; chemical purity > 99%; more than 99% ee
[ column: chiraltek AY-3,3 μm,100mm x4.6mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 5): rt=1.52 min; m/z=472 (m+h) + 。
Example 39 (enantiomer 2):
2- [ (3R) -3- (difluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001563
Yield: 101mg
R t =6.03 min; the chemical purity is more than 96 percent; > 94% ee
[ column: chiraltek AY-3,3 μm,100mm x 4.6mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 5): r is R t ＝1.52min；m/z＝472(M+H) + 。
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 1.11-1.22 (m, 1H), 1.37-1.54 (m, 3H), 1.62-1.72 (m, 2H), 1.73-1.81 (m, 2H), 1.88-1.99 (m, 1H), 2.10-2.21 (m, 2H), 2.47-2.60 (m, 1H, partially masked by DMSO), 2.72 (br.d, 1H), 2.79 (br.d, 1H), 3.05 (br.t, 2H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 5.82-6.06 (m, 1H), 7.84 (s, 1H), 7.93 (td, 1H), 8.47 (d, 1H), 8.75 (t, 1H).
Example 40 and example 41
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomers 1 and 2)
Figure BDA0004107514540001571
144mg (0.32 mmol) of racemic N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (example 6) are separated on the chiral phase into the enantiomers by preparative HPLC [ column: daicel Chiralpak IG,5 μm,250mm×20mm; mobile phase: ethanol; flow rate: 15ml/min; UV detection: 220nm; temperature: 70 ℃ ]:
Example 40 (enantiomer 1):
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001572
Yield: 71mg
R t =10.94 min; chemical purity 99%;99% ee
[ column: daicel Chiralcel IG,5 μm,250 mm. Times.4.6 mm; mobile phase: ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 40 ℃; UV detection: 235nm ].
LC-MS (method 1): r is R t ＝0.85min；m/z＝454(M+H) + 。
Example 41 (enantiomer 2):
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (fluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001581
Yield: 70mg of
R t =12.21 min; chemical purity 99%;99% ee
[ column: daicel Chiralcel IG,5 μm,250 mm. Times.4.6 mm; mobile phase: ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 40 ℃; UV detection: 235nm ].
LC-MS (method 1): r is R t ＝0.84min；m/z＝454(M+H) + 。
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): 0.94-1.10 (m, 1H), 1.35-1.55 (m, 3H), 1.61 (br.d, 2H), 1.72-1.92 (m, 3H), 2.03 (t, 1H), 2.16 (br.t, 1H), 2.47-2.57 (m, 1H, partially masked by DMSO), 2.65-2.76 (m, 1H), 2.80 (br.d, 1H), 3.05 (br.t, 2H), 3.94 (br.d, 2H), 4.19-4.29 (m, 1H), 4.31-4.41 (m, 1H)，4.53(br.d，2H)，7.83(s，1H)，7.87-7.96(m，1H)，8.47(d，1H)，8.71(t，1H)。
Example 42 and example 43
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomers 1 and 2)
Figure BDA0004107514540001582
143mg (0.29 mmol) of N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (trifluoromethyl) I1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (example 5) are separated on the chiral phase by preparative HPLC into the enantiomer [ column: daicel Chiralpak IG,5 μm,250mm x 20mm; mobile phase: ethanol; flow rate: 15ml/min; UV detection: 220nm; temperature: 40 ℃ ]:
example 42 (enantiomer 1):
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3S) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001583
Yield: 67mg
Rt=11.22 min; chemical purity 99%;99% ee
[ column: daicel Chiralcel IG,5 μm,250 mm. Times.4.6 mm; mobile phase: ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 50 ℃; UV detection: 235nm ].
LC-MS (method 1): r is R t ＝0.97min；m/z＝490(M+H) + 。
Example 43 (enantiomer 2):
n- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (trifluoromethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001591
Yield: 67mg
R t =11.87 min; chemical purity 99%; > 96% ee
[ column: daicel Chiralcel IG,5 μm,250 mm. Times.4.6 mm; mobile phase: ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 50 ℃; UV detection: 235nm ].
LC-MS (method 1): r is R t ＝0.96min；m/z＝490(M+H) + 。
1H-NMR(500MHz，DMSO-d 6 ，δ/ppm)：1.14-1.27(m，1H)，1.39-1.57(m，3H)，1.65-1.73(m，1H)，1.74-1.82(m，2H)，1.82-1.88(m，1H)，2.06-2.20(m，2H)，2.32-2.44(m，1H)，2.61(br.t，1H)，2.81(br.d，1H)，2.96(br.d，1H)，3.05(td，2H)，3.95(br.d，2H)，4.53(br.d，2H)，7.83(s，1H)，7.88-7.94(m，1H)，8.47(d，1H)，8.71(t，1H)。
Example 44 and example 45
2- {3- [ (3, 3-Difluorocyclobutyl) methoxy ] [1,4 '-bipiperidine ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomers 1 and 2)
Figure BDA0004107514540001592
251mg (0.46 mmol) of 2- {3- [ (3, 3-difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (example 7) was separated in the chiral phase by preparative HPLC into the enantiomers [ column: daicel Chiralcel OD-H,5 μm,250mmx 20mm; mobile phase: n-heptane/2-propanol +0.2% diethylamine 50:50; flow rate: 20ml/min; UV detection: 220nm; temperature: 30 ℃ ]:
example 44 (enantiomer 1):
2- { (3R) -3- [ (3, 3-Difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001601
Yield: 93mg
R t =1.50 min; chemical purity > 99%;99% ee
[ column: phenomenex Cellulose-1,3 μm,50 mm. Times.4.6 mm; mobile phase: n-heptane/2-propanol +0.2% diethylamine); flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 4): r is R t ＝0.63min；m/z＝542(M+H) + 。
Example 45 (enantiomer 2):
2- { (3S) -3- [ (3, 3-Difluorocyclobutyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001602
Yield: 86mg
R t =2.21 min; chemical purity > 99%;99% ee
[ column: phenomenex Cellulose-1,3 μm,50 mm. Times.4.6 mm; mobile phase: n-heptane/2-propanol +0.2% diethylamine); flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 4): rt=0.62 min; m/z=542 (m+h) + 。
1 H-NMR(400MHz，DMSO-d 6 Delta/ppm): 1.02-1.12 (m, 1H), 1.30-1.42 (m, 1H), 1.42-1.56 (m, 2H), 1.58-1.68 (m, 1H), 1.72-1.83 (m, 2H), 1.85-1.94 (m, 1H), 1.99 (br.t, 1H), 2.10 (br.t, 1H), 2.21-2.38 (m, 3H), 2.48-2.62 (m, 3H, partially masked by DMSO), 2.62-2.70 (m, 1H), 2.95 (br.d, 1H), 3.04 (br.t, 2H), 3.22-3.34 (m, 1H, partially masked by H) 2 O mask), 3.40-3.51 (m, 2H)，3.95(br.d，2H)，4.53(br.d，2H)，7.83(s，1H)，7.87-7.95(m，1H)，8.47(d，1H)，8.71(t，1H)。
Example 46 and example 47
N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide (diastereomers 1 and 2)
Figure BDA0004107514540001611
51mg (0.11 mmol) of the diastereomeric mixture N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide (example 30) are separated in the chiral phase into the diastereomers by means of preparative HPLC [ column: daicel Chiralcel OX-H5 μm,250 mm. Times.20 mm; mobile phase: n-heptane/ethanol 50:50; flow rate: 20ml/min; UV detection: 220nm; temperature: 40 ℃ ]:
Example 46 (diastereomer 1):
yield: 20mg of
R t =1.32 min; chemical purity > 99%;99% ee
[ column: daicel Chiralpak OX-3,3 μm,50 mm. Times.4.6 mm; mobile phase: n-heptane/ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 1): r is R t ＝1.22min；m/z＝449(M+H) + 。
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.66 (m, 9H, including at 1.42 (d, 3H)), 1.70-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.56 (m, 1H, partially masked by DMSO), 2.68-2.80 (m, 2H), 3.00-3.09 (m, 2H), 3.95 (br.t, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.19-7.25 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).
Example 47 (diastereomer 2):
yield: 19mg of
R t =1.78 min; chemical purity > 99%;99% ee
[ column: daicel Chiralpak OX-3,3 μm,50 mm. Times.4.6 mm; mobile phase: n-heptane/ethanol +0.2% diethylamine; flow rate: 1ml/min; temperature: 25 ℃; UV detection: 220nm ].
LC-MS (method 1): r is R t ＝1.19min；m/z＝449(M+H)+。
1 H-NMR(600MHz，DMSO-d 6 Delta/ppm): 0.76-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.67 (m, 9H, including at 1.42 (d, 3H)), 1.72-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.60 (m, 1H, partially masked by DMSO), 2.69-2.81 (m, 2H), 3.05 (br.t, 2H), 3.89-4.00 (m, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.18-7.26 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).
Example 48
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001621
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (124 mg, 370. Mu. Mol) and rac-3- (methoxymethyl) -1,4' -bipiperidine dihydrochloride (123 mg, 75% purity, 285. Mu. Mol) were combined and stirred in 2ml sodium carbonate solution (2.0 ml,2.0M,4.0 mmol) at 120℃for 1 hour. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water: mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12 ml 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 60.0mg (purity 100%, 35% of theory) of the target compound.
LC-MS (method 4): rt=0.51 min; MS (ESIpos): m/z=466 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.903(0.47)，0.918(0.53)，1.389(0.42)，1.409(0.44)，1.432(0.44)，1.445(0.53)，1.452(0.88)，1.460(0.62)，1.465(0.64)，1.472(0.94)，1.480(0.56)，1.578(1.12)，1.596(1.00)，1.716(0.49)，1.755(1.11)，1.774(0.96)，1.878(0.66)，1.895(1.06)，1.912(0.56)，2.091(0.43)，2.106(0.78)，2.109(0.78)，2.124(0.42)，2.483(0.43)，2.520(0.42)，2.706(0.61)，2.724(0.57)，2.795(0.63)，2.809(0.61)，3.018(0.74)，3.023(0.88)，3.040(1.54)，3.043(1.52)，3.060(0.87)，3.064(0.76)，3.129(0.51)，3.144(1.48)，3.157(1.78)，3.159(1.83)，3.169(1.56)，3.175(0.63)，3.184(0.52)，3.200(16.00)，3.920(1.12)，3.941(1.06)，4.521(2.22)，4.530(2.22)，7.828(5.37)，7.893(0.59)，7.897(0.63)，7.910(0.90)，7.913(0.94)，7.925(0.60)，7.929(0.62)，8.465(2.32)，8.468(2.28)，8.701(0.73)，8.710(1.47)，8.720(0.71)。
Example 49
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -3- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1,2, 4-oxadiazole-5-carboxamide
Figure BDA0004107514540001631
N, N-diisopropylethylamine (44 μl,250 mmol) and propylphosphonic anhydride (66 μl,50% in ethyl acetate, 110 μmol) were added to a solution of 3- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1,2, 4-oxadiazole-5-carboxylic acid (25.0 mg,84.9 μmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (24.0 mg,110 μmol) in 1ml acetonitrile and the mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 7.00mg (purity 100%, 20% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.96min；MS(ESIpos)：m/z＝421[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.780(0.59)，0.786(0.66)，0.813(14.94)，0.824(16.00)，0.841(0.69)，0.847(0.57)，1.370(0.56)，1.377(0.45)，1.391(1.47)，1.411(1.58)，1.431(1.38)，1.437(1.22)，1.457(2.49)，1.472(2.70)，1.493(1.64)，1.498(1.66)，1.510(1.34)，1.516(1.25)，1.522(1.29)，1.527(1.13)，1.567(1.91)，1.583(1.19)，1.588(1.52)，1.618(1.61)，1.639(1.55)，1.744(2.47)，1.760(5.97)，1.778(4.64)，2.040(1.21)，2.055(2.23)，2.074(1.19)，2.449(1.19)，2.467(2.20)，2.487(1.30)，2.732(2.07)，2.746(3.74)，2.763(1.77)，2.931(2.53)，2.949(4.76)，2.969(2.54)，3.905(3.81)，3.927(3.64)，4.586(6.49)，4.596(6.41)，7.930(1.47)，7.934(1.53)，7.949(2.60)，7.962(1.51)，7.966(1.50)，8.476(5.87)，8.479(5.69)，9.631(1.76)，9.641(3.44)，9.651(1.75)。
Example 50
diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001641
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (200 mg, 599. Mu. Mol) and diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride (142 mg, 519. Mu. Mol) were combined and stirred in 1.2ml of sodium carbonate solution (1.2 ml,2.0M,2.4 mmol) at 120℃for 30 minutes. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water: mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12 ml 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 192mg (purity 100%, 70% of theory) of the target compound.
LC-MS (method 4): r is R t ＝0.54min；MS(ESIpos)：m/z＝454[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.807(8.04)，0.818(8.54)，0.823(9.19)，0.833(9.26)，0.845(1.26)，0.851(1.27)，0.865(0.57)，0.872(0.48)，1.375(0.72)，1.396(0.88)，1.425(0.72)，1.513(0.76)，1.524(0.78)，1.550(1.22)，1.572(1.24)，1.578(1.30)，1.600(1.01)，1.624(1.99)，1.639(1.94)，1.647(1.92)，1.795(1.24)，1.817(0.99)，1.923(0.96)，1.932(0.79)，1.940(1.73)，1.948(1.32)，1.958(1.00)，1.964(0.66)，2.226(1.04)，2.245(1.98)，2.264(1.01)，2.424(0.59)，2.653(0.51)，2.730(2.22)，2.744(2.48)，2.801(1.20)，2.813(1.28)，3.129(1.00)，3.134(1.13)，3.154(1.85)，3.169(1.17)，3.214(0.84)，3.226(1.61)，3.235(1.14)，3.247(1.52)，3.261(0.83)，3.286(0.43)，3.705(1.26)，3.726(1.18)，4.117(0.76)，4.123(0.88)，4.136(1.42)，4.144(1.43)，4.156(0.80)，4.162(0.74)，4.527(5.54)，4.536(5.52)，4.691(0.60)，4.698(0.88)，4.705(1.12)，4.713(0.79)，4.719(0.57)，4.773(0.59)，4.779(0.81)，4.787(1.13)，4.794(0.85)，4.801(0.57)，7.844(16.00)，7.899(1.65)，7.903(1.77)，7.916(2.25)，7.918(2.38)，7.931(1.68)，7.935(1.72)，8.468(6.33)，8.472(6.30)，8.754(1.79)，8.764(3.76)，8.773(1.86)。
Example 51
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540001651
190mg of diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [ (3R) -3 '-fluoro-3-methyl [1,4' -bipiperidine]-1' -yl]Separation of the 1, 3-thiazole-5-carboxamide into stereoisomers by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540001652
Chiralpak IA,5 μm,250x 20mm; mobile phase: 100% ethanol +0.2% diethylamine; the flow rate is 20ml/min; detecting at 60 ℃): 220 nm). Stereoisomers with retention time 7.873 min were collected (HPLC: column
Figure BDA0004107514540001653
Chiralpak IE5 μm, flow 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to yield 88mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.93min；MS(ESIpos)：m/z＝454[M+H] + 。
1 H.NMR(500MHz，DMSO-d 6 )δ[ppm]：δ8.72(t，1H)，8.47(d，1H)，7.94-7.89(m，1H)，7.82(s，1H)，5.10(d，1H)，4.53(d，2H)，4.18(m，1H)，4.00(m，1H)，3.32(dd，1H)，3.18-3.11(m，1H)，2.82(m，2H)，2.70-2.57(m，1H)，2.20-2.14(m，1H)，1.94-1.83(m，2H)，1.70-1.51(m，4H)，1.43-1.33(m，1H)，0.88-0.78(m，1H)，0.82(d，3H)。
Example 52
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540001661
190mg of diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [ (3R) -3 '-fluoro-3-methyl [1,4' -bipiperidine]-1' -yl]Separation of the 1, 3-thiazole-5-carboxamide into stereoisomers by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540001663
Chiralpak IA,5 μm,250x 20mm; mobile phase: 100% ethanol +0.2% diethylamine; the flow rate is 20ml/min; detecting at 60 ℃): 220 nm). Stereoisomers with retention time of 10.179 min were collected (HPLC: column
Figure BDA0004107514540001664
Chiralpak IE5 μm, flow 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to yield 91mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.93min；MS(ESIpos)：m/z＝454[M+H] + 。
1 H.NMR(500MHz，DMSO-d 6 )δ[ppm]：δ8.72(t，1H)，8.47(d，1H)，7.94-7.89(m，1H)，7.82(s，1H)，5.10(d，1H)，4.53(d，2H)，4.18(m，1H)，4.00(m，1H)，3.32(dd，1H)，3.19-3.12(m，1H)，2.82(d br，2H)，2.70-2.57(m，1H)，2.21-2.15(m，1H)，1.94-1.84(m，2H)，1.70-1.56(m，3H)，1.53-1.38(m，2H)，0.88-0.78(m，1H)，0.81(d，3H)。
Example 53
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001662
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (9.7. Mu.l, 170. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- (4-Oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-4-methylazepan (32.1 mg, 284. Mu. Mol) in 2.5ml dichloromethane and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213. Mu. Mol) was added, and the mixture was stirred at room temperature. After 2 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100x30mm, mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min, room temperature, wavelength: 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 43.0mg (purity 100%, 67% of theory) of the title compound.
LC-MS (method 1): rt=0.98 min; MS (ESIpos): m/z=450 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.874(16.00)，0.886(15.94)，1.166(1.35)，1.173(2.14)，1.180(1.44)，1.189(2.16)，1.195(1.69)，1.206(1.49)，1.223(2.09)，1.240(2.28)，1.257(1.07)，1.262(0.94)，1.417(1.40)，1.431(3.73)，1.438(3.97)，1.451(4.78)，1.457(4.63)，1.471(3.48)，1.478(2.98)，1.491(1.13)，1.499(0.91)，1.566(1.97)，1.572(1.71)，1.590(2.05)，1.609(1.83)，1.632(4.40)，1.642(4.13)，1.649(3.78)，1.727(2.59)，1.747(4.36)，1.766(2.28)，2.519(3.82)，2.525(2.88)，2.567(1.76)，2.574(1.84)，2.588(3.16)，2.594(2.42)，2.603(2.38)，2.610(2.22)，2.636(3.23)，2.645(6.11)，2.653(6.12)，2.664(4.76)，2.675(3.65)，2.684(1.53)，3.020(3.04)，3.038(5.45)，3.059(3.16)，3.327(0.99)，3.921(4.02)，3.941(3.84)，4.523(7.77)，4.532(7.71)，7.819(13.98)，7.877(1.85)，7.881(1.92)，7.895(3.21)，7.897(3.22)，7.909(1.86)，7.913(1.83)，8.458(6.41)，8.462(6.13)，8.662(2.36)，8.671(4.40)，8.680(2.29)。
Example 54
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (3-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001681
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (9.7. Mu.l, 170. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-3-methylazepan hydrochloride (42.5 mg, 284. Mu. Mol) in 2.5ml of dichloromethane was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213. Mu. Mol) was added, and the mixture was stirred at room temperature. After 2 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBRID C18 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v)) The method comprises the steps of carrying out a first treatment on the surface of the Total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, and completely injecting sample; gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 40.0mg (purity 100%, 63% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.97min；MS(ESIpos)：m/z＝450[M+H] +
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.813(15.55)，0.823(16.00)，1.127(0.63)，1.144(1.47)，1.151(1.29)，1.168(1.44)，1.409(0.90)，1.422(3.44)，1.428(3.08)，1.440(5.99)，1.449(4.90)，1.461(3.41)，1.468(2.80)，1.481(1.05)，1.561(1.44)，1.573(1.70)，1.589(0.97)，1.610(3.22)，1.629(4.80)，1.637(3.85)，1.648(2.15)，1.738(3.86)，1.757(3.39)，2.188(2.20)，2.202(2.24)，2.210(2.45)，2.224(2.31)，2.569(0.93)，2.578(1.13)，2.591(2.08)，2.600(2.09)，2.609(1.71)，2.630(1.60)，2.639(4.89)，2.644(4.73)，2.660(4.71)，2.664(4.78)，2.683(1.26)，3.018(2.77)，3.035(5.01)，3.039(4.91)，3.056(2.76)，3.256(0.45)，3.933(3.56)，3.953(3.40)，4.524(7.13)，4.533(7.07)，7.819(13.92)，7.880(1.63)，7.883(1.71)，7.896(2.87)，7.899(2.96)，7.911(1.68)，7.915(1.70)，8.460(6.36)，8.463(6.29)，8.662(2.12)，8.672(4.27)，8.681(2.16)。
Example 55
diamix-N- [ l- (3, 5-difluoropyridin-2-yl) ethyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001691
N, N-diisopropylethylamine (182 μl,105 μmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride (100 mg,262 μmol) and rac-1- (3, 5-difluoropyridin-2-yl) ethylamine (45.5 mg,288 μmol) in 5ml acetonitrile and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm, mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min, room temperature, wavelength: 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 12.0mg (purity 100%, 10% of theory) of the target compound.
LC-MS (method 1): rt=1.02 min; MS (ESIpos): m/z=450 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.788(0.72)，0.811(14.96)，0.822(16.00)，0.843(0.68)，1.389(1.55)，1.409(1.64)，1.440(14.70)，1.452(14.49)，1.480(2.90)，1.502(2.05)，1.564(1.99)，1.586(1.51)，1.615(1.65)，1.636(1.56)，1.735(1.85)，1.753(4.97)，1.779(3.32)，2.032(1.18)，2.049(2.19)，2.069(1.17)，2.423(0.65)，2.466(1.28)，2.653(0.49)，2.716(2.04)，2.731(3.74)，2.748(1.88)，3.015(2.36)，3.036(4.36)，3.057(2.38)，3.224(0.42)，3.249(0.65)，3.316(0.89)，3.913(2.65)，5.317(0.57)，5.329(2.00)，5.341(3.01)，5.353(1.96)，7.861(1.44)，7.876(2.73)，7.893(1.49)，7.912(11.30)，8.468(5.59)，8.531(3.80)，8.543(3.75)。
Example 56
N- [ (5-chloro-1, 3-thiazol-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001701
N, N-diisopropylethylamine (230 μl,1.3 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride (100 mg,262 μmol) and 1- (5-chloro-1, 3-thiazol-2-yl) methylamine hydrochloride (53.2 mg,288 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 14.0mg (purity 100%, 12% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.00min；MS(ESIpos)：m/z＝440[M+H] + 。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：-0.149(0.78)，0.146(0.87)，0.811(14.60)，0.827(16.00)，1.475(2.13)，1.498(2.88)，1.605(1.71)，1.729(1.52)，1.756(3.69)，1.802(2.53)，2.051(1.90)，2.366(1.52)，2.710(2.65)，3.041(2.14)，3.067(3.51)，3.098(1.95)，3.937(2.72)，3.966(2.56)，4.573(8.03)，4.588(7.85)，7.731(15.89)，7.837(15.31)，9.094(1.71)，9.108(3.31)，9.122(1.68)。
Example 57
N- [ (5-fluoro-2-thienyl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001711
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride (100 mg,262 μmol) and 1- (5-fluoro-2-thienyl) methylamine (37.7 mg,288 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 12.0mg (purity 100%, 11% of theory) of the target compound.
LC-MS (method 1): rt=1.09 min; MS (ESIpos): m/z=423 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.783(0.52)，0.790(0.59)，0.813(15.03)，0.824(16.00)，0.843(0.57)，0.850(0.47)，1.370(0.50)，1.391(1.25)，1.411(1.35)，1.431(0.57)，1.454(0.72)，1.474(1.98)，1.494(2.47)，1.511(1.80)，1.529(0.96)，1.540(0.58)，1.565(1.59)，1.571(1.23)，1.582(0.96)，1.587(1.28)，1.616(1.32)，1.637(1.24)，1.737(1.79)，1.754(3.23)，1.771(4.08)，1.788(2.51)，2.036(1.05)，2.050(1.91)，2.054(1.88)，2.069(1.04)，2.471(1.13)，2.477(0.78)，2.722(1.66)，2.734(3.05)，2.752(1.45)，3.031(1.84)，3.035(2.16)，3.052(3.73)，3.055(3.70)，3.072(2.12)，3.077(1.85)，3.257(0.59)，3.278(0.99)，3.927(2.78)，3.948(2.65)，4.394(4.22)，4.398(4.54)，4.404(4.54)，4.408(4.29)，6.512(3.08)，6.516(3.37)，6.518(3.69)，6.522(3.52)，6.660(2.25)，6.666(4.14)，6.672(2.16)，7.780(13.01)，8.786(1.58)，8.796(3.27)，8.806(1.66)。
Example 58
2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- (pyridin-4-ylmethyl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001721
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride (100 mg,262 μmol) and 1- (pyridin-4-yl) methylamine (31.1 mg,288 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v), total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 7.00mg (purity 100%, 7% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.48min；MS(ESIneg)：m/z＝398[M-H]-。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：0.776(0.54)，0.796(1.55)，0.812(14.81)，0.828(16.00)，0.855(0.65)，0.865(0.55)，0.950(1.20)，0.966(1.16)，1.356(0.44)，1.387(1.16)，1.417(1.35)，1.446(1.24)，1.474(2.25)，1.499(2.83)，1.525(1.95)，1.534(1.73)，1.563(1.86)，1.604(1.82)，1.645(1.30)，1.731(1.87)，1.758(4.55)，1.783(2.68)，1.796(2.56)，2.030(1.05)，2.052(1.88)，2.058(1.85)，2.080(1.06)，2.366(0.57)，2.473(1.30)，2.725(2.30)，2.741(2.70)，3.031(2.07)，3.057(3.71)，3.088(2.13)，3.932(2.97)，3.965(2.79)，4.401(6.43)，4.416(6.43)，7.269(4.34)，7.280(4.58)，7.849(13.88)，8.505(1.83)，8.800(1.58)，8.815(3.27)，8.830(1.59)。
Example 59
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001731
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (118 mg, 353. Mu. Mol) and rac-3- [ (2, 2-trifluoroethoxy) methyl]1,4' -bipiperidine dihydrochloride (164 mg, 75% pure, 348. Mu. Mol) was combined and stirred in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min: room temperature, wavelength 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase) A and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 56.0mg (purity 100%, 30% of theory) of the target compound.
LC-MS (method 5): rt=1.64 min; MS (ESIpos): m/z=534 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.937(0.65)，0.955(1.56)，0.970(1.59)，0.988(0.67)，1.381(0.58)，1.402(1.31)，1.420(1.45)，1.431(1.19)，1.439(1.22)，1.452(2.08)，1.458(1.80)，1.465(1.92)，1.471(3.02)，1.478(1.98)，1.485(1.91)，1.492(2.15)，1.505(0.81)，1.512(0.59)，1.589(3.51)，1.605(3.09)，1.767(4.45)，1.952(1.98)，1.969(3.12)，1.986(1.74)，2.133(1.36)，2.148(2.51)，2.166(1.33)，2.513(2.55)，2.689(1.93)，2.707(1.83)，2.776(2.08)，2.791(2.00)，3.029(2.57)，3.049(4.90)，3.070(2.56)，3.425(0.45)，3.443(7.66)，3.454(8.96)，3.925(3.82)，3.947(3.63)，3.976(3.33)，3.992(9.56)，4.008(9.29)，4.023(3.00)，4.525(7.17)，4.534(7.14)，7.824(16.00)，7.877(1.74)，7.881(1.86)，7.897(2.97)，7.909(1.76)，7.913(1.81)，8.458(6.85)，8.462(6.81)，8.666(2.27)，8.676(4.58)，8.685(2.26)。
Example 60
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [1- (fluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001741
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (75.5 mg, 226. Mu. Mol) and rac-3- ({ [1- (fluoromethyl) cyclopropyl)]Methoxy } methyl) -1,4' -bipiperidine dihydrochloride (133 mg) was combined and stirred at 120℃in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 The SO4 was dried, the desiccant was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 10.5mg (purity 100%, 9% of theory) of the target compound.
LC-MS (method 5): rt=1.65 min; MS (ESIpos): m/z=538 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.500(0.62)，0.507(0.85)，0.526(0.86)，0.531(1.03)，1.601(0.40)，3.051(0.52)，3.242(1.08)，3.253(1.11)，3.279(2.71)，3.289(16.00)，3.923(0.41)，3.943(0.40)，4.219(0.96)，4.301(0.97)，4.524(0.77)，4.533(0.76)，7.824(1.56)，8.459(0.67)，8.463(0.68)，8.675(0.48)。
Example 61
rac-2- [3- ({ [1- (difluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001751
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 300. Mu. Mol) and rac-3- ({ [1- (difluoromethyl) cyclopropyl)]Methoxy } methyl) -1,4' -bipiperidine dihydrochloride (112 mg) was combined and stirred at 120℃in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and taken up in dichloroAnd (5) extracting methane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection: gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml.10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 49.8mg (purity 100%, 30% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.71min；MS(ESIpos)：m/z＝556[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.608(6.75)，0.611(6.72)，0.725(3.50)，0.733(9.17)，0.735(8.79)，0.743(2.54)，0.904(0.57)，0.921(1.21)，0.936(1.35)，0.955(0.59)，1.372(0.53)，1.391(1.17)，1.411(1.22)，1.437(0.65)，1.444(0.72)，1.456(1.67)，1.466(1.85)，1.476(2.47)，1.485(1.95)，1.496(1.74)，1.515(0.52)，1.587(2.51)，1.592(2.61)，1.599(2.32)，1.722(1.44)，1.739(1.01)，1.759(2.61)，1.781(2.25)，1.909(1.70)，1.926(2.76)，1.943(1.48)，2.109(1.17)，2.125(2.16)，2.142(1.16)，2.486(1.43)，2.522(1.19)，2.699(1.73)，2.718(1.60)，2.791(1.81)，2.806(1.75)，3.029(2.22)，3.050(4.07)，3.071(2.19)，3.237(7.84)，3.248(8.49)，3.384(0.66)，3.403(16.00)，3.422(0.65)，3.922(3.21)，3.943(3.05)，4.524(6.21)，4.533(6.24)，5.805(2.61)，5.901(5.22)，5.996(2.47)，7.824(12.56)，7.878(1.45)，7.882(1.55)，7.897(2.60)，7.910(1.53)，7.914(1.57)，8.458(5.72)，8.462(5.73)，8.666(1.94)，8.675(3.99)，8.684(2.01)。
Example 62
rac-N- [ (3, 5-difluoropyridine x 2 x) methyl ] -2- [3- ({ [1- (trifluoromethyl) cyclopropyl ] methoxy } methyl) [1,4 '-bipiperidine ]/1' -yl ] -1, 3-thiazolx 5 x carboxamide
Figure BDA0004107514540001761
2-bromo-N- [ (3, 5 x difluoropyridin-2-yl) methyl]-1, 3-thiazole 5 x carboxamide (110 mg,329 μmol) and rac-3- ({ [1 x (trifluoromethyl) cyclopropyl)]Methoxy } methyl) 1,4' -bipiperidine dihydrochloride (129 mg) was combined and stirred at 120 ℃ in 2ml sodium carbonate solution (2 ml,2.0m,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 56.0mg (purity 100%, 30% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.78min；MS(ESIpos)：m/z＝574[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.808(7.29)，0.908(0.91)，0.926(1.41)，0.934(3.81)，0.942(9.64)，0.953(2.74)，1.393(1.17)，1.411(1.23)，1.432(0.90)，1.440(0.99)，1.452(1.48)，1.460(2.20)，1.470(2.07)，1.480(2.36)，1.500(0.99)，1.584(2.93)，1.600(2.53)，1.721(1.36)，1.757(2.85)，1.779(2.43)，1.907(1.65)，1.925(2.68)，1.941(1.46)，2.110(1.18)，2.125(2.13)，2.144(1.12)，2.482(1.29)，2.519(1.31)，2.699(1.69)，2.717(1.59)，2.788(1.78)，2.804(1.71)，3.031(2.12)，3.052(3.86)，3.073(2.08)，3.233(0.60)，3.252(5.22)，3.262(7.02)，3.456(0.42)，3.475(16.00)，3.495(0.43)，3.920(3.15)，3.942(3.00)，4.524(6.08)，4.533(6.04)，7.824(11.55)，7.879(1.35)，7.883(1.50)，7.897(2.52)，7.911(1.45)，7.914(1.45)，8.459(5.46)，8.462(5.45)，8.666(1.84)，8.675(3.81)，8.685(1.89)。
Example 63
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3, 3-dimethyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001771
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]1, 3-thiazole-5-carboxamide (50.0 mg, 150. Mu. Mol) and 3, 3-dimethyl-1, 4' -bipiperidine dihydrochloride (52.3 mg) were initially added to 1ml of water. Sodium carbonate (63.4 mg, 599. Mu. Mol) was added to the solution, and the mixture was stirred at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min31ml, mobile phase A2 to 10min from 39ml to 15ml and mobile phase B from 31ml to 55ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 37.0mg (purity 100%, 55% of theory) of the target compound.
LC-MS (method 1): rt=0.95 min; MS (ESIpos): m/z=450 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.882(16.00)，1.150(0.79)，1.160(1.14)，1.170(0.89)，1.468(1.40)，1.479(1.32)，1.488(1.33)，1.729(0.86)，1.747(0.73)，2.097(2.01)，2.392(0.76)，2.473(0.61)，3.034(0.54)，3.038(0.63)，3.056(1.10)，3.076(0.63)，3.080(0.54)，3.902(0.87)，3.923(0.82)，4.520(1.58)，4.529(1.56)，7.826(3.86)，7.894(0.42)，7.898(0.44)，7.911(0.63)，7.913(0.67)，7.926(0.43)，7.930(0.43)，8.464(1.64)，8.468(1.59)，8.699(0.51)，8.709(1.03)，8.719(0.50)。
Example 64
2- [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001781
2-bromo-N- [ (3, 5 x difluoropyridine x 2 x yl) methyl group]-1, 3-thiazole 5-carboxamide (200 mg,599 μmol) and 5 (piperidin-4-yl) 5 azaspiro [2.5]]Octane dihydrochloride (180 mg) was initially added to 2ml of water. Sodium carbonate (254 mg,2.39 mmol) was added and the mixture was stirred at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are in the whole) Constant flow rates of 5ml/min each during each run time). The product-containing fractions were combined and lyophilized. This gives 108mg (purity 100%, 40% of theory) of the target compound.
LC-MS (method 1): rt=0.90 min; MS (ESIpos): m/z=448 [ m+h ]] + 。
1 H.NMR(500MHz，DMSO-d 6 )δ[ppm]： δ 8.70(t，1H)，8.46(d，1H)，7.94-7.89(m，1H)，7.82(s，1H)，4.52(d，2H)，3.90(d br，2H)，3.08-3.02(m，2H)，2.47-2.40(m，3H)，2.19(S，2H)1.77(d br，2H)，1.57(m，2H)，1.50-1.40(m，2H)，1.24(t，2H)，0.28-0.21(m，4H)。
Example 65
rac-2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001791
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and rac-1, 1-difluoro-5- (piperidin-4-yl) -5-azaspiro [2.5]]Octane dihydrochloride (104 mg) was initially added to 1ml of water. Sodium carbonate (127 mg,1.20 mmol) was added and the mixture was stirred at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml, mobile phase A10 to 12min 0ml and mobile phase B70 ml mobile phase C and mobile phase D are in Constant flow rates of 5ml/min each over the run time). The product-containing fractions were combined and lyophilized. This gives 62.0mg (purity 100%, 43% of theory) of the target compound.
LC-MS (method 5): rt=1.56 min; MS (ESIpos): m/z=484 [ m+h ]] + 。
1 H.NMR(500MHz，DMSO-d 6 )δ[ppm]：δ8.71(t，1H)，8.46(d，1H)，7.94-7.89(m，1H)，7.83(s，1H)，4.52(d，2H)，3.92(d br，2H)，3.10-3.02(m，2H)，2.67-2.57(m，3H)，2.44-2.37(m，2H)，1.78(t br，2H)，1.60(m，1H)，1.53-1.42(m，5H)，1.26-1.14(m，2H)。
Example 66
rac-2- [3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001792
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (12. Mu.l, 210. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-3- (cyclobutylmethoxy) piperidine hydrochloride (58.4 mg, 284. Mu. Mol) in 5ml of dichloromethane was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170. Mu. Mol) was added, and the mixture was stirred at room temperature. After 1.5 hours, more sodium triacetoxyborohydride (36.1 mg, 170. Mu. Mol) was added and the mixture was stirred at room temperature. After 2 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase is concentrated on a rotary evaporator and the residue is dissolved in DMSO and purified by preparative HPLC (apparatus: waters Prep LC/MS system, column: XBRID C18 μm 100x30mm, mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min, room temperature, wavelength: 200-400 n) m, completely sampling; gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 5.00mg (purity 100%, 7% of theory) of the target compound.
LC-MS (method 1): rt=1.22 min; MS (ESIpos): m/z=506 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.009(0.53)，1.016(0.59)，1.029(1.45)，1.036(1.37)，1.053(1.53)，1.066(0.71)，1.074(0.56)，1.316(0.60)，1.337(1.44)，1.357(1.50)，1.376(0.65)，1.453(0.95)，1.472(2.73)，1.492(2.83)，1.511(1.08)，1.610(1.84)，1.632(1.99)，1.643(3.00)，1.657(3.90)，1.672(3.26)，1.685(1.32)，1.759(3.93)，1.781(4.11)，1.796(2.12)，1.808(3.21)，1.822(4.29)，1.836(2.48)，1.840(1.45)，1.849(0.87)，1.854(0.98)，1.867(0.44)，1.890(1.64)，1.904(1.62)，1.919(1.99)，1.931(3.81)，1.945(6.23)，1.953(3.44)，1.961(4.23)，1.974(1.09)，2.059(1.35)，2.073(2.48)，2.092(1.33)，2.403(1.00)，2.415(2.19)，2.427(2.80)，2.440(2.11)，2.452(0.94)，2.564(1.15)，2.652(2.37)，2.669(1.88)，2.942(1.96)，2.954(1.82)，3.018(2.55)，3.038(4.84)，3.058(2.54)，3.205(1.36)，3.214(1.73)，3.221(2.34)，3.229(1.64)，3.237(1.32)，3.244(0.74)，3.293(0.74)，3.354(1.90)，3.365(2.08)，3.370(5.42)，3.382(7.32)，3.394(5.38)，3.399(2.01)，3.410(1.64)，3.929(3.33)，3.949(3.21)，4.520(6.95)，4.530(6.93)，7.828(16.00)，7.894(1.82)，7.898(1.94)，7.913(2.92)，7.926(1.83)，7.930(1.88)，8.465(7.15)，8.468(7.02)，8.701(2.24)，8.711(4.57)，8.721(2.24)。
Example 67
rac-2- [3- (cyclopropylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001811
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (60.8 mg, 182. Mu. Mol) and rac-3- (cyclopropylmethoxy) -1,4' -bipiperidine dihydrochloride (50.0 mg) were combined and stirred at 120℃in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 20.0mg (purity 100%, 22% of theory) of the target compound.
LC-MS (method 1): rt=1.06 min; MS (ESIpos): m/z=492 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.114(2.20)，0.122(7.19)，0.129(7.41)，0.137(2.33)，0.410(2.11)，0.416(6.34)，0.419(6.12)，0.430(6.52)，0.433(6.08)，0.439(1.85)，0.923(1.53)，0.935(2.28)，0.947(1.44)，1.024(0.64)，1.038(1.55)，1.060(1.59)，1.075(0.78)，1.316(0.66)，1.336(1.50)，1.357(1.60)，1.376(0.70)，1.451(1.00)，1.471(2.74)，1.482(2.39)，1.491(2.85)，1.499(1.88)，1.511(1.16)，1.610(1.97)，1.633(1.67)，1.758(3.91)，1.777(3.38)，1.886(1.71)，1.900(1.62)，1.926(2.05)，1.942(3.48)，1.959(2.11)，2.062(1.42)，2.077(2.57)，2.095(1.40)，2.423(0.62)，2.520(1.90)，2.558(1.22)，2.652(2.62)，2.669(2.02)，2.943(2.00)，2.956(1.92)，3.018(2.70)，3.037(5.11)，3.057(2.70)，3.240(13.81)，3.251(14.04)，3.264(2.67)，3.271(1.87)，3.280(1.60)，3.288(1.56)，3.344(0.84)，3.927(3.48)，3.946(3.30)，4.520(7.38)，4.529(7.39)，7.827(16.00)，7.895(1.83)，7.899(1.91)，7.915(3.15)，7.927(1.89)，7.931(1.94)，8.465(7.46)，8.469(7.11)，8.702(2.42)，8.711(4.84)，8.721(2.39)。
Example 68
rac-2- {3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001821
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and rac-3- [ (cyclobutoxy) methyl]1,4' -bipiperidine dihydrochloride (144 mg) was combined and stirred at 120℃in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength: 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 38.0mg (purity 100%, 25% of theory) of the target compound.
LC-MS (square)Method 1): r is R t ＝1.11min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.880(0.72)，0.897(1.70)，0.913(1.85)，0.932(0.78)，1.361(0.72)，1.381(1.75)，1.387(1.75)，1.404(2.77)，1.418(3.45)，1.435(3.99)，1.443(2.72)，1.450(3.84)，1.463(3.80)，1.483(2.61)，1.574(4.23)，1.588(6.01)，1.604(4.37)，1.622(1.30)，1.659(1.93)，1.753(6.08)，1.761(6.58)，1.768(6.61)，1.774(6.32)，1.804(0.59)，1.883(2.18)，1.900(3.68)，1.917(1.93)，2.099(5.66)，2.113(7.26)，2.131(2.89)，2.522(1.55)，2.691(2.43)，2.709(2.25)，2.788(2.57)，2.802(2.45)，3.022(3.24)，3.041(6.13)，3.061(3.30)，3.084(4.70)，3.098(4.88)，3.101(5.01)，3.111(4.67)，3.117(2.12)，3.127(1.53)，3.294(0.66)，3.357(0.67)，3.793(0.85)，3.805(3.00)，3.818(4.35)，3.829(2.93)，3.842(0.82)，3.924(4.69)，3.945(4.39)，4.520(8.81)，4.529(8.73)，7.827(16.00)，7.896(1.92)，7.911(3.69)，7.926(1.86)，8.464(7.34)，8.467(7.27)，8.700(2.70)，8.709(5.37)，8.719(2.66)。
Example 69
rac-2- {3- [ (cyclopropylmethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001831
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (50.9 mg, 152. Mu. Mol) and rac-3- [ (cyclopropylmethoxy) methyl]1,4' -bipiperidine dihydrochloride (44.0 mg) was combined and stirred in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MSSystem, column: XBIdge C18 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80 vol%/20 vol%); total flow rate: 80ml/min; room temperature; the wavelength is 200-400nm, and the sample is completely injected; gradient curve: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 15.0mg (purity 100%, 19% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.12min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.118(2.25)，0.126(9.10)，0.134(9.17)，0.142(2.22)，0.419(2.38)，0.426(7.33)，0.427(7.44)，0.439(7.57)，0.441(7.33)，0.448(1.98)，0.889(0.73)，0.904(1.72)，0.922(2.00)，0.947(2.51)，0.958(2.65)，0.969(1.73)，0.978(0.81)，1.369(0.75)，1.388(1.75)，1.409(1.76)，1.428(1.26)，1.435(1.20)，1.447(2.46)，1.467(3.67)，1.487(2.56)，1.507(0.71)，1.573(2.43)，1.579(2.59)，1.593(4.27)，1.609(2.19)，1.705(1.94)，1.766(3.63)，1.894(2.27)，1.911(3.77)，1.928(1.94)，2.099(1.66)，2.114(3.06)，2.132(1.60)，2.526(1.44)，2.701(2.49)，2.719(2.26)，2.802(2.62)，2.817(2.51)，3.026(3.23)，3.045(6.22)，3.064(3.23)，3.147(0.41)，3.165(13.68)，3.176(13.45)，3.191(1.65)，3.206(5.08)，3.219(9.08)，3.228(5.08)，3.234(1.95)，3.244(1.30)，3.296(0.60)，3.923(4.82)，3.944(4.45)，4.521(8.96)，4.530(8.75)，7.827(16.00)，7.893(2.03)，7.896(2.11)，7.911(3.75)，7.924(2.05)，7.928(2.02)，8.464(8.06)，8.467(7.70)，8.700(2.76)，8.710(5.37)，8.719(2.62)。
Example 70
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ 3-ethoxy [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001841
Acetic acid (12. Mu.l, 210. Mu. Mol) was added to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-3-ethoxypiperidine (36.7 mg, 284. Mu. Mol) in 5ml of dichloromethane was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170. Mu. Mol) was added, and the mixture was stirred at room temperature. After 4 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm, mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 15.0mg (purity 100%, 23% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.94min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.021(0.44)，1.035(0.92)，1.042(0.86)，1.057(8.38)，1.068(16.00)，1.080(8.12)，1.320(0.40)，1.342(0.87)，1.360(0.89)，1.472(1.63)，1.492(1.70)，1.511(0.65)，1.611(1.11)，1.617(0.92)，1.627(0.80)，1.634(1.00)，1.759(2.28)，1.778(1.99)，1.887(0.97)，1.901(0.93)，1.935(1.27)，1.951(2.00)，1.967(1.30)，2.062(0.81)，2.076(1.56)，2.080(1.49)，2.095(0.84)，2.523(1.00)，2.561(0.76)，2.652(1.54)，2.670(1.13)，2.938(1.14)，2.949(1.07)，3.019(1.52)，3.038(2.87)，3.058(1.56)，3.221(0.46)，3.228(0.88)，3.235(1.05)，3.244(1.46)，3.251(1.03)，3.259(0.83)，3.266(0.45)，3.346(0.70)，3.351(0.76)，3.423(0.98)，3.427(1.06)，3.434(1.21)，3.438(4.04)，3.450(6.06)，3.461(4.04)，3.465(1.20)，3.473(1.09)，3.477(0.96)，3.927(1.96)，3.948(1.87)，4.521(4.14)，4.530(4.13)，7.828(11.05)，7.895(1.16)，7.899(1.24)，7.912(1.70)，7.914(1.80)，7.927(1.19)，7.931(1.24)，8.465(4.56)，8.469(4.52)，8.702(1.37)，8.712(2.80)，8.721(1.38)。
Example 71
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {4- [ (3R) -3-methylpiperidin-1-yl ] azepan-1-yl } -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001851
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (70.0 mg, 209. Mu. Mol) and 4- [ (3R) -3-methylpiperidin-1-yl]Azepane dihydrochloride (48.8 mg) was initially added to 1ml of water. Sodium carbonate (88.8 mg, 838. Mu. Mol) was added to the solution, and the mixture was stirred at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The fractions containing the product were pooled and lyophilized . This gives 38.0mg (purity 100%, 40% of theory) of the target compound.
LC-MS (method 5): rt=1.80 min; MS (ESIpos): m/z=450 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.763(0.66)，0.790(11.01)，0.794(11.81)，0.800(12.77)，0.805(11.44)，1.354(1.54)，1.368(3.05)，1.373(2.83)，1.387(2.70)，1.409(1.20)，1.488(1.52)，1.534(2.35)，1.556(2.32)，1.593(2.70)，1.614(2.01)，1.688(1.57)，1.705(1.69)，1.722(0.79)，1.740(1.27)，1.757(4.10)，1.773(4.04)，1.790(2.51)，1.894(3.01)，2.065(1.69)，2.383(1.59)，2.399(2.60)，2.417(1.27)，2.599(4.31)，2.615(3.21)，3.354(1.52)，3.378(2.77)，3.397(2.73)，3.655(1.75)，4.519(7.77)，4.528(7.74)，7.825(16.00)，7.893(1.86)，7.897(1.91)，7.909(3.18)，7.924(1.95)，7.928(1.92)，8.463(7.52)，8.467(7.26)，8.646(2.37)，8.656(4.74)，8.665(2.33)。
Example 72
2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -N- [ (6-methylpyridin-3-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001861
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2 [ (3R) 3-methyl [1,4 '. Dipiperidin ] -1' -yl ] -1, 3-thiazole 5-carboxylic acid dihydrochloride (100 mg,262 μmol) and 1- (6-methylpyridin-3-yl) methylamine (35.1 mg,288 μmol) in 5ml acetonitrile and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% by volume), total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 19.0mg (purity 100%, 18% of theory) of the target compound.
LC-MS (method 1): rt=0.55 min; MS (ESIneg): m/z=412 [ m-H ] -.
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.799(0.74)，0.811(7.56)，0.822(8.04)，1.388(0.65)，1.408(0.66)，1.466(1.03)，1.490(1.23)，1.508(0.93)，1.519(0.60)，1.525(0.54)，1.564(0.83)，1.580(0.51)，1.586(0.67)，1.615(0.70)，1.636(0.67)，1.732(0.88)，1.750(1.63)，1.767(2.09)，1.783(1.34)，2.032(0.52)，2.046(0.96)，2.050(0.94)，2.065(0.52)，2.431(16.00)，2.470(0.64)，2.720(0.87)，2.734(1.57)，2.751(0.74)，3.026(1.11)，3.044(1.97)，3.064(1.13)，3.924(1.42)，3.945(1.35)，4.349(3.74)，4.359(3.72)，7.196(2.33)，7.210(2.52)，7.556(1.53)，7.560(1.54)，7.570(1.45)，7.573(1.43)，7.795(6.86)，8.366(2.40)，8.370(2.40)，8.711(0.92)，8.721(1.84)，8.731(0.92)。
Example 73
N-benzyl-2 [ (3R) 3-methyl [1,4 '-bipiperidine ]. Times.1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001871
N, N-diisopropylethylamine (100 μl,580 μmol) and propylphosphonic anhydride (47 μl,50% in ethyl acetate, 160 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-hydrochloride (50.0 mg,145 μmol) and 1-phenylmethylamine (17 μl,160 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml, constant flow rates of 10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D each 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 25.0mg (purity 100%, 43% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.04min；MS(ESIpos)：m/z＝399[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.785(0.53)，0.791(0.62)，0.815(14.94)，0.826(16.00)，0.844(0.63)，0.851(0.53)，1.372(0.52)，1.393(1.35)，1.407(0.92)，1.413(1.45)，1.433(0.62)，1.458(0.78)，1.477(2.21)，1.496(2.75)，1.513(2.00)，1.531(1.04)，1.542(0.63)，1.567(1.74)，1.572(1.34)，1.583(1.05)，1.589(1.39)，1.617(1.47)，1.638(1.39)，1.739(1.91)，1.757(3.65)，1.773(4.17)，1.788(2.83)，2.038(1.12)，2.053(2.08)，2.056(2.04)，2.071(1.14)，2.471(1.17)，2.477(0.82)，2.724(1.87)，2.736(3.43)，2.754(1.63)，3.030(2.28)，3.048(4.18)，3.068(2.31)，3.929(3.15)，3.951(2.98)，4.387(7.95)，4.397(7.93)，7.225(1.22)，7.237(3.31)，7.248(2.13)，7.277(4.54)，7.289(8.70)，7.310(6.60)，7.322(7.31)，7.336(2.52)，7.822(11.60)，8.684(1.68)，8.694(3.35)，8.704(1.70)。
Example 74
diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- ({ [ 3-fluorobutyl ] oxy } methyl) [1,4 '] bipiperidinyl ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001881
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and diamix-3- [ (3-fluorobutoxy) methyl]1,4' -bipiperidine dihydrochloride (92.4 mg) was combined and stirred in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 45.0mg (purity 100%, 29% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.10min；MS(ESIpos)：m/z＝526[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.894(0.51)，0.910(1.21)，0.927(1.31)，0.946(0.55)，1.231(1.01)，1.249(9.88)，1.259(9.97)，1.289(9.92)，1.300(9.69)，1.367(0.53)，1.387(1.24)，1.407(1.28)，1.426(0.92)，1.434(0.92)，1.445(1.68)，1.455(1.93)，1.465(2.52)，1.476(2.04)，1.485(1.80)，1.493(0.81)，1.504(0.53)，1.574(1.89)，1.589(2.71)，1.595(2.68)，1.698(1.15)，1.710(1.65)，1.721(1.89)，1.729(1.76)，1.734(1.74)，1.742(2.56)，1.752(3.56)，1.758(3.71)，1.768(3.79)，1.771(3.66)，1.777(3.74)，1.780(3.74)，1.787(2.97)，1.799(1.97)，1.808(0.76)，1.900(1.21)，1.915(2.14)，1.931(1.08)，2.101(1.15)，2.115(2.11)，2.133(1.13)，2.485(1.36)，2.522(1.14)，2.698(1.78)，2.716(1.64)，2.788(1.77)，2.804(1.72)，3.023(2.35)，3.043(4.47)，3.064(2.31)，3.181(0.85)，3.197(1.94)，3.209(5.46)，3.221(4.27)，3.231(1.98)，3.237(1.28)，3.247(0.88)，3.368(0.58)，3.378(1.01)，3.384(1.18)，3.387(0.79)，3.394(1.92)，3.401(3.11)，3.411(4.27)，3.421(2.19)，3.428(1.41)，3.431(1.34)，3.441(1.12)，3.444(0.79)，3.457(0.56)，3.921(3.36)，3.943(3.18)，4.521(6.49)，4.530(6.43)，4.687(0.71)，4.698(0.98)，4.708(0.96)，4.718(0.66)，4.769(0.74)，4.780(1.12)，4.790(1.10)，4.800(0.71)，7.828(16.00)，7.892(1.77)，7.896(1.83)，7.909(2.66)，7.911(2.78)，7.924(1.78)，7.928(1.78)，8.463(7.00)，8.467(6.72)，8.701(2.17)，8.710(4.39)，8.720(2.11)。
Example 75
rac-2- (3- { [ (3, 3-difluorocyclobutyl) methoxy ] methyl } [1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001901
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and rac-3- { [ (3, 3-difluorocyclobutyl) methoxy]Methyl } -1,4' -bipiperidine dihydrochloride (286 mg) was combined and stirred at 120℃in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 The drying agent is dried, filtered off and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 47 ml)2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 42.0mg of the target compound (purity 100%, 25% of theory).
LC-MS (method 1): r is R t ＝1.20min；MS(ESIpos)：m/z＝556[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.911(0.78)，0.928(1.72)，0.945(1.85)，0.963(0.81)，1.374(0.78)，1.394(1.76)，1.414(1.76)，1.434(1.28)，1.441(1.17)，1.454(2.40)，1.466(2.42)，1.473(3.58)，1.486(2.51)，1.493(2.58)，1.596(3.83)，1.731(2.04)，1.759(4.07)，1.917(2.39)，1.935(3.91)，1.952(2.04)，2.110(1.73)，2.126(3.13)，2.144(1.58)，2.261(0.89)，2.274(1.32)，2.295(3.70)，2.317(5.95)，2.336(3.61)，2.485(2.03)，2.521(1.62)，2.564(2.23)，2.574(2.41)，2.578(2.59)，2.587(3.86)，2.601(2.66)，2.611(2.16)，2.701(2.47)，2.719(2.29)，2.789(2.63)，2.804(2.46)，3.029(3.08)，3.050(5.72)，3.070(3.05)，3.231(0.68)，3.247(9.82)，3.258(11.25)，3.358(0.88)，3.381(7.63)，3.389(5.10)，3.405(0.86)，3.921(4.65)，3.943(4.34)，4.524(8.79)，4.534(8.71)，7.823(16.00)，7.878(1.95)，7.882(2.02)，7.897(3.64)，7.910(1.95)，7.914(2.00)，8.458(7.56)，8.462(7.46)，8.665(2.65)，8.674(5.27)，8.684(2.62)。
Example 76
N- [ (3-fluoropyridin-4-yl) methyl ] -2- [ (3R) 3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001911
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2 [ (3R) 3-methyl [1,4 '] bipiperidinyl ] 1' -yl ] -1, 3-thiazole ] 5-hydrochloride (100 mg,262 μmol) and 1- (3-fluoropyridin-4-yl) methylamine (36.3 mg,288 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm; mobile phase: water: mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 21.0mg (purity 100%, 19% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.82min；MS(ESIneg)：m/z＝416[M-H]-.
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.788(0.58)，0.814(15.04)，0.825(16.00)，0.842(0.70)，1.371(0.56)，1.392(1.36)，1.412(1.46)，1.432(0.62)，1.473(2.29)，1.493(2.88)，1.511(2.09)，1.568(1.79)，1.589(1.42)，1.618(1.54)，1.640(1v49)，1.738(1.72)，1.756(3.14)，1.773(4.60)，1.792(2.86)，2.037(1.07)，2.056(2.00)，2.071(1.12)，2.425(0.56)，2.520(1.70)，2.653(0.50)，2.726(1.87)，2.738(3.35)，2.757(1.60)，3.042(2.38)，3.059(4.22)，3.080(2.39)，3.287(0.93)，3.937(3.04)，3.959(2.92)，4.466(7.56)，4.476(7.60)，7.336(2.33)，7.345(3.35)，7.355(2.45)，7.859(12.63)，8.383(4.52)，8.391(4.59)，8.511(6.60)，8.513(6.51)，8.819(1.88)，8.829(3.81)，8.839(1.85)。
Example 77
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2, 2-trifluoroethoxy) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001921
Acetic acid (12. Mu.l, 210. Mu. Mol) was added to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-3- (2, 2-trifluoroethoxy) piperidine (52.0 mg, 284. Mu. Mol) in 5ml of dichloromethane was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170. Mu. Mol) was added, and the mixture was stirred at room temperature. After 1.5 hours, more sodium triacetoxyborohydride (36.1 mg, 170. Mu. Mol) was added and the mixture was stirred at room temperature. After 2 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters prepLC/MS system, column: XBridge C18. Mu.m.100×30mm, mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min, room temperature, wavelength 200-400nm, complete sample injection, gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 7.00mg (purity 100%, 9% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.06min；MS(ESIpos)：m/z＝520[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.124(1.34)，1.147(1.39)，1.160(0.64)，1.343(1.36)，1.365(1.39)，1.475(1.80)，1.496(2.67)，1.516(1.84)，1.637(1.77)，1.658(1.46)，1.758(3.69)，1.777(3.15)，1.916(1.56)，2.015(1.74)，2.032(2.94)，2.048(1.77)，2.106(1.29)，2.120(2.39)，2.138(1.28)，2.423(0.93)，2.565(2.35)，2.584(0.93)，2.640(1.95)，2.652(2.04)，2.658(1.76)，2.969(1.90)，2.981(1.80)，3.025(2.41)，3.045(4.81)，3.065(2.50)，3.282(1.41)，3.289(0.62)，3.345(1.02)，3.350(0.92)，3.447(1.28)，3.455(1.66)，3.462(2.19)，3.470(1.56)，3.478(1.17)，3.934(3.16)，3.953(3.03)，4.042(1.46)，4.049(1.60)，4.058(4.17)，4.065(4.12)，4.073(4.05)，4.081(3.91)，4.096(1.27)，4.520(6.74)，4.529(6.68)，7.828(16.00)，7.895(1.76)，7.900(1.83)，7.915(2.87)，7.927(1.78)，7.931(1.82)，8.465(6.78)，8.469(6.85)，8.703(2.10)，8.712(4.35)，8.722(2.21)。
Example 78
N- [ (4, 6-dimethylpyridin-3-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001931
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (86 μl,50% in ethyl acetate, 290 μmol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-hydrochloride (100 mg,262 μmol) and 1- (4, 6-dimethylpyridin-3-yl) methylamine (39.2 mg,288 μmol) in 5ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20%) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 8.00mg (purity 100%, 7% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.53min；MS(ESIneg)：m/z＝426[M-H]-.
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：-0.149(0.57)，0.146(0.57)，0.808(8.12)，0.825(8.74)，1.382(0.62)，1.413(0.76)，1.422(0.69)，1.465(1.17)，1.486(1.46)，1.494(1.54)，1.513(0.97)，1.559(0.97)，1.601(0.93)，1.640(0.67)，1.724(1.01)，1.751(2.71)，1.776(1.44)，1.786(1.36)，2.023(0.58)，2.045(0.99)，2.073(0.56)，2.263(16.00)，2.327(0.71)，2.366(1.24)，2.386(15.84)，2.459(0.67)，2.669(0.76)，2.674(0.57)，2.710(2.03)，2.736(1.41)，3.013(1.10)，3.039(1.91)，3.070(1.13)，3.294(2.40)，3.916(1.56)，3.949(1.50)，4.352(3.75)，4.366(3.82)，7.051(3.86)，7.802(8.23)，8.243(4.42)，8.518(0.89)，8.532(1.87)，8.546(0.89)。
Example 79
N- [ (4-chloro-1-methyl-1H-pyrazol-5-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540001941
30.9mg (0.10 mmol) of 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid, 53.2mg (0.14 mmol) of HATU and 50. Mu.l of 4-methylmorpholine are dissolved in 0.7ml of DMF and stirred at RT for 30 minutes. The solution was then added to 29.2mg (0.20 mmol) of 1- (4-chloro-1-methyl-1H-pyrazol-5-yl) methylamine, which had been initially added to one well of a 96-well multi-layer titration plate, and the multi-well plate was sealed and shaken overnight at RT, then 0.2ml of water was added, the mixture was filtered, and the filtrate was separated into its components by preparative LC-MS using one of the following methods:
preparation type LC-MS method:
MS instrument: waters, HPLC instrument: waters (column WatersX-Bridge C18, 19mmx50mm,5 μm, mobile phase A: water+0.375% ammonia, mobile phase B: acetonitrile (ULC) +0.375% ammonia, gradient, flow rate: 40ml/min, UV detection: DAD;210-400 nm).
Or alternatively:
MS instrument: waters, HPLC instrument: waters (column Phenomenex luna 5. Mu.C 18 (2) 100A, AXIATech.50x21.2mm, mobile phase A: water+0.0375% formic acid, mobile phase B: acetonitrile (ULC) +0.0375% formic acid, gradient, flow rate: 40ml/min, UV detection: DAD;210-400 nm).
27.7mg (63% of theory, 96% pure) of the title compound are thus obtained.
LC-MS (method 6, ESIpos): r is R t ＝0.69min；m/z＝437(M+H) + 。
1 H-NMR(500MHz，DMSO-d 6 Delta/ppm): 0.90 (d, 3H), 1.03-1.15 (m, 1H), 1.60-1.90 (m, 6H), 2.05-2.14 (m, 2H), 2.56-2.65 (m, 1H), 2.80-2.91 (m, 1H), 3.12 (br.t, 2H), 3.33 (br.d, 1H), 3.36-3.51 (m, 1H, partially covered by H 2 O mask), 3.82 (s, 3H), 4.08 (br.d, 2H), 4.45 (d, 2H), 7.49 (s, 1H), 7.85 (s, 1H), 8.68 (t, 1H), 8.96-9.04 (m, 1H).
The following compounds of examples 80 to 98 were prepared in analogy to the parallel synthesis of example 79 from 2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid and the appropriate amine or salt thereof:
Figure BDA0004107514540001951
Figure BDA0004107514540001961
Figure BDA0004107514540001971
Figure BDA0004107514540001981
Figure BDA0004107514540001991
Figure BDA0004107514540002001
example 99
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002011
45mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002012
Chiralpak IG,5 μm,250X 20mm; mobile phase: 100% ethanol +0.2% diethylamine; the flow rate is 15ml/min; and (3) detecting the temperature of 55 ℃): 220 nm). The enantiomer with retention time 10.838 min was collected (HPLC: column
Figure BDA0004107514540002013
Chiralpak IE 5 μm, flow 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to give 23mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.89min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.911(0.66)，0.927(0.72)，1.392(0.58)，1.410(0.63)，1.436(0.52)，1.457(1.21)，1.477(1.28)，1.497(0.51)，1.582(1.53)，1.598(1.39)，1.719(0.66)，1.758(1.52)，1.778(1.33)，1.887(0.89)，1.904(1.48)，1.921(0.77)，2.097(0.59)，2.114(1.12)，2.132(0.59)，2.707(0.80)，2.726(0.79)，2.796(0.89)，2.809(0.83)，3.026(1.13)，3.044(2.13)，3.065(1.14)，3.136(0.55)，3.151(1.82)，3.164(3.39)，3.173(1.89)，3.189(0.57)，3.203(16.00)，3.919(1.63)，3.941(1.53)，4.522(2.97)，4.531(2.96)，7.822(5.28)，7.879(0.69)，7.897(1.23)，7.910(0.69)，8.459(2.58)，8.462(2.46)，8.663(0.90)，8.673(1.76)，8.682(0.91)。
Example 100
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (methoxymethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002014
45mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002021
Chiralpak IG,5 μm,250X 20mm; mobile phase: 100% ethanol +0.2% diethylamine; the flow rate is 15ml/min; and (3) detecting the temperature of 55 ℃): 220 nm). The enantiomer with retention time 11.879 min was collected (HPLC: column
Figure BDA0004107514540002022
Chiralpak IE 5 μm, flow 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to give 19mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.87min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.912(0.54)，0.927(0.59)，1.393(0.47)，1.411(0.49)，1.437(0.45)，1.458(0.99)，1.469(0.70)，1.478(1.03)，1.497(0.43)，1.582(1.26)，1.599(1.14)，1.720(0.53)，1.759(1.25)，1.778(1.08)，1.887(0.77)，1.904(1.24)，1.921(0.65)，2.098(0.48)，2.113(0.90)，2.132(0.48)，2.521(0.54)，2.708(0.69)，2.725(0.65)，2.795(0.72)，2.809(0.70)，3.027(0.95)，3.044(1.74)，3.065(0.96)，3.136(0.52)，3.151(1.62)，3.164(3.04)，3.173(1.73)，3.179(0.62)，3.189(0.51)，3.203(16.00)，3.920(1.30)，3.942(1.23)，4.523(2.44)，4.532(2.44)，7.822(5.22)，7.878(0.60)，7.882(0.63)，7.897(1.01)，7.910(0.61)，7.914(0.60)，8.459(2.33)，8.462(2.25)，8.664(0.75)，8.673(1.50)，8.683(0.73)。
Example 101
ent-2- {3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002023
28mg of rac-2- {3- [ (cyclobutoxy) methyl][1,4' -bipiperidines]-1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the 1, 3-thiazole-5-carboxamide into enantiomers by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002024
ChiralpakIG,5 μm,250x20mm; mobile phase: 100% ethanol +0.2% diethylamine; the flow rate is 15ml/min; and (3) detecting at 35 ℃ and: 220 nm). The enantiomer with retention time 13.192min was collected (HPLC: column +.>
Figure BDA0004107514540002025
Chiralpak IG 5 μm, flow rate 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 40 ℃; and (3) detection: 220 nm). The solvent was removed to give 11mg (99% ee) of the title compound.
LC-MS (method 4): r is R t ＝0.61min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.890(0.70)，0.905(1.48)，0.923(1.66)，0.941(0.75)，1.236(0.70)，1.365(0.68)，1.384(1.52)，1.391(1.55)，1.405(2.41)，1.409(2.43)，1.422(3.30)，1.426(2.37)，1.436(2.51)，1.439(3.65)，1.453(3.11)，1.457(3.28)，1.469(3.44)，1.477(2.22)，1.488(2.22)，1.576(3.79)，1.592(5.01)，1.608(3.25)，1.626(1.13)，1.661(1.66)，1.736(0.87)，1.757(5.34)，1.765(5.46)，1.772(5.55)，1.779(5.30)，1.809(0.51)，1.892(2.15)，1.909(3.40)，1.926(1.85)，2.088(1.66)，2.092(2.09)，2.105(5.13)，2.120(5.86)，2.132(1.97)，2.136(2.23)，2.421(0.40)，2.523(1.40)，2.693(2.11)，2.711(1.92)，2.788(2.15)，2.803(2.11)，3.027(2.76)，3.045(5.15)，3.065(2.86)，3.077(1.68)，3.093(4.48)，3.106(7.14)，3.117(4.69)，3.123(1.81)，3.132(1.31)，3.260(0.75)，3.797(0.82)，3.810(2.77)，3.822(3.96)，3.834(2.63)，3.846(0.73)，3.924(4.03)，3.945(3.80)，4.523(7.43)，4.532(7.38)，7.822(16.00)，7.878(1.81)，7.882(1.92)，7.897(3.16)，7.910(1.88)，7.913(1.87)，8.458(7.01)，8.462(6.89)，8.664(2.34)，8.673(4.66)，8.683(2.34)。
Example 102
ent-2- {3- [ (cyclobutoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002031
28mg of rac-2- {3- [ (cyclobutoxy) methyl][1,4' -bipiperidines]-1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002032
Chiralpak IG,5 μm,250X20mm; mobile phase: 100% of BAlcohol +0.2% diethylamine; the flow rate is 15ml/min; and (3) detecting at 35 ℃ and: 220 nm). The enantiomer with retention time 15.649min was collected (HPLC: column +. >
Figure BDA0004107514540002033
Chiralpak IG 5 μm, flow rate 1ml/min; mobile phase: 100% ethanol +0.2% diethylamine; the temperature is 40 ℃; and (3) detection: 220 nm). The solvent was removed to give 15mg (99% ee) of the title compound.
LC-MS (method 4): r is R t ＝0.61min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.892(0.70)，0.911(1.47)，0.925(1.61)，0.944(0.75)，1.181(0.58)，1.236(0.75)，1.393(1.83)，1.406(2.67)，1.410(2.79)，1.423(3.49)，1.427(2.71)，1.437(2.88)，1.441(3.93)，1.454(3.44)，1.458(3.62)，1.471(3.83)，1.479(2.52)，1.490(2.38)，1.578(4.21)，1.593(5.37)，1.609(3.64)，1.627(1.42)，1.664(1.80)，1.737(1.27)，1.758(5.60)，1.766(5.97)，1.773(5.87)，1.781(5.68)，1.810(0.82)，1.898(1.60)，1.915(2.56)，1.931(1.34)，2.089(2.00)，2.093(2.40)，2.107(5.04)，2.111(4.26)，2.117(4.59)，2.122(4.87)，2.136(2.03)，2.423(0.43)，2.572(0.60)，2.697(1.87)，2.716(1.71)，2.793(2.04)，2.808(1.91)，3.028(2.85)，3.046(5.10)，3.066(3.05)，3.078(2.04)，3.094(4.70)，3.108(6.61)，3.118(4.75)，3.124(2.06)，3.134(1.53)，3.798(0.78)，3.811(2.64)，3.822(3.74)，3.835(2.51)，3.847(0.68)，3.926(3.99)，3.947(3.69)，4.524(7.26)，4.533(7.00)，7.824(16.00)，7.878(2.01)，7.882(2.03)，7.895(2.96)，7.898(2.98)，7.910(1.94)，7.914(1.86)，8.459(7.08)，8.463(6.55)，8.665(2.41)，8.675(4.52)，8.684(2.21)。
Example 103
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-isopropyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002041
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (9.7. Mu.l, 170. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50.0 mg, 142. Mu. Mol) and rac-3-isopropylpiperidine (36.1 mg, 284. Mu. Mol) in 3ml of dichloromethane was stirred at room temperature for 6 hours. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213. Mu. Mol) was added, and the mixture was stirred at room temperature. After 15 hours, saturated NaHCO was added 3 The solution was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100x30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: total flow rate of acetonitrile/water (80% v/20%) 80ml/min; room temperature; wavelength 200-400nm, complete sample injection. Gradient curve: mobile phase A0 to 2 min 47ml mobile phase B0 to 2 min 23ml mobile phase A2 to 10 min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12 min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 23.0mg (purity 100%, 35% of theory) of the title compound.
LC-MS (method 5): r is R t ＝1.85min；MS(ESIpos)：m/z＝464[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.837(14.82)，0.843(15.99)，0.848(16.00)，0.854(15.31)，0.877(1.10)，0.883(1.12)，0.897(1.16)，0.903(1.14)，0.917(0.49)，0.923(0.43)，1.160(0.54)，1.171(0.93)，1.177(1.09)，1.183(0.97)，1.188(1.09)，1.195(0.85)，1.206(0.49)，1.334(0.44)，1.354(1.17)，1.375(1.58)，1.387(1.58)，1.398(2.24)，1.409(1.94)，1.420(1.12)，1.441(0.42)，1.448(0.49)，1.461(1.12)，1.467(1.32)，1.486(1.96)，1.506(1.42)，1.525(0.55)，1.533(0.43)，1.600(1.43)，1.606(1.16)，1.616(0.92)，1.622(1.22)，1.627(0.94)，1.647(1.19)，1.668(1.14)，1.765(1.59)，1.778(2.27)，1.792(1.35)，1.866(1.66)，1.883(3.02)，1.901(1.55)，2.024(1.02)，2.038(1.80)，2.042(1.78)，2.057(1.01)，2.524(1.03)，2.733(1.42)，2.751(1.37)，2.770(1.47)，2.786(1.40)，3.020(1.59)，3.026(1.23)，3.041(2.88)，3.057(1.18)，3.063(1.59)，3.931(2.24)，3.948(2.14)，4.523(4.92)，4.532(4.94)，7.821(13.40)，7.879(1.40)，7.883(1.52)，7.895(2.03)，7.898(2.11)，7.910(1.43)，7.914(1.50)，8.459(5.28)，8.462(5.28)，8.662(1.61)，8.672(3.25)，8.681(1.63)。
Example 104
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002051
33mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [4- (4-methylazepan-1-yl) piperidin-1-yl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002052
Chiralpak AY-H,5 μm,250x 20mm; mobile phase: 70% n-heptane, mobile phase B:30% ethanol+0.2% diethylamine in B; the flow rate is 15ml/min; temperature 60C, detection: 220 nm). The enantiomer with retention time 10.241 min was collected (HPLC: column +.>
Figure BDA0004107514540002061
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:70% n-heptane, mobile phase B:30% ethanol+0.2% diethylamine in B; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to give 15mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.98min；MS(ESIpos)：m/z＝450[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.876(16.00)，0.887(15.94)，1.181(1.40)，1.200(1.81)，1.223(2.27)，1.240(2.37)，1.257(1.01)，1.446(2.85)，1.460(3.55)，1.479(2.38)，1.572(1.57)，1.595(1.81)，1.613(1.45)，1.619(1.81)，1.642(3.31)，1.648(3.08)，1.655(2.78)，1.756(2.90)，2.422(0.41)，2.611(1.54)，2.668(2.96)，3.023(2.75)，3.040(5.00)，3.061(2.82)，3.926(3.42)，3.946(3.24)，4.523(7.45)，4.532(7.44)，7.820(14.18)，7.879(1.77)，7.882(1.83)，7.895(3.04)，7.910(1.83)，7.914(1.85)，8.458(6.84)，8.462(6.66)，8.663(2.10)，8.672(4.24)，8.682(2.21)。
Example 105
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [4- (4-methylazepan-1-yl) piperidin-1-yl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002062
33mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [4- (4-methylazepan-1-yl) piperidin-1-yl ]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002063
Chiralpak AY-H,5 μm,250x 20mm; mobile phase: 70% n-heptane, mobile phase B:30% ethanol+0.2% diethylamine in B; the flow rate is 15ml/min; detecting at 60 ℃): 220 nm). The enantiomer with retention time 10.783 min was collected (HPLC: column +.>
Figure BDA0004107514540002064
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:70% n-heptane, mobile phase B:30% ethanol+0.2% diethylamine in B; the temperature is 60 ℃; and (3) detection: 220 nm). The solvent was removed to give 16mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝0.98min；MS(ESIpos)：m/z＝450[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.876(15.76)，0.887(16.00)，1.181(1.39)，1.201(1.73)，1.223(2.16)，1.240(2.40)，1.257(1.05)，1.444(2.79)，1.458(3.56)，1.477(2.43)，1.572(1.52)，1.596(1.76)，1.641(3.34)，1.647(3.12)，1.655(2.79)，1.754(3.00)，2.610(1.55)，2.664(3.12)，3.023(2.70)，3.040(4.97)，3.060(2.82)，3.258(0.86)，3.324(0.78)，3.924(3.44)，3.944(3.25)，4.522(7.39)，4.531(7.46)，7.819(14.10)，7.879(1.72)，7.882(1.79)，7.895(3.01)，7.910(1.67)，7.914(1.76)，8.458(6.66)，8.462(6.47)，8.663(2.16)，8.672(4.25)，8.682(2.15)。
Example 106
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002071
53mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- {3- [ (2, 2-trifluoroethoxy) methyl][1,4' -bipiperidines]Separation of the enantiomers by chiral HPLC of the 1' -yl } -1, 3-thiazole-5-carboxamide (preparative HPLC: column
Figure BDA0004107514540002072
Chiralpak AY-H,5 μm,250x 20mm; mobile phase a:55% n-heptane, mobile phase B:45% ethanol +0.2% diethylamine in B; the flow rate is 15ml/min; detecting at 60 ℃): 220 nm). The enantiomer with retention time 5.622 min was collected (HPLC: column +. >
Figure BDA0004107514540002073
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; the temperature is 70 ℃; detection of:220 nm). The solvent was removed to give 27mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.09min；MS(ESIpos)：m/z＝534[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.957(1.60)，0.972(1.65)，0.991(0.73)，1.405(1.42)，1.422(1.56)，1.433(1.26)，1.453(2.17)，1.474(3.10)，1.493(2.23)，1.591(3.88)，1.609(3.56)，1.771(4.73)，1.974(1.76)，2.155(1.88)，2.697(1.60)，2.780(1.80)，2.796(1.72)，3.030(2.88)，3.051(5.58)，3.071(2.93)，3.322(0.44)，3.426(0.55)，3.443(8.06)，3.454(9.47)，3.926(4.21)，3.948(4.04)，3.977(3.49)，3.993(10.05)，4.008(9.84)，4.024(3.21)，4.524(8.20)，4.533(8.19)，7.823(16.00)，7.879(1.88)，7.882(2.06)，7.898(3.42)，7.910(1.91)，7.914(2.03)，8.458(7.35)，8.462(7.51)，8.667(2.44)，8.676(4.94)，8.685(2.45)。
Example 107
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- {3- [ (2, 2-trifluoroethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002081
53mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- {3- [ (2, 2-trifluoroethoxy) methyl][1,4' -bipiperidines]Separation of the enantiomers by chiral HPLC of the 1' -yl } -1, 3-thiazole-5-carboxamide (preparative HPLC: column
Figure BDA0004107514540002082
Chiralpak AY-H,5 μm,250x 20mm; mobile phase a:55% n-heptane, mobile phase B:45% ethanol +0.2% diethylamine in B; the flow rate is 15ml/min; detecting at 60 ℃): 220 nm). The enantiomer with retention time 6.301 min was collected (HPLC: column +.>
Figure BDA0004107514540002083
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; the temperature is 70 ℃; and (3) detection: 220 nm). The solvent was removed to give 25mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.08min；MS(ESIpos)：m/z＝534[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.956(1.27)，0.972(1.33)，1.403(1.14)，1.422(1.29)，1.433(1.11)，1.453(1.79)，1.473(2.52)，1.493(1.88)，1.592(3.06)，1.608(2.89)，1.770(3.84)，1.973(1.45)，2.154(1.54)，2.693(1.28)，2.780(1.42)，2.794(1.42)，3.030(2.30)，3.050(4.43)，3.071(2.43)，3.426(0.52)，3.443(6.29)，3.454(7.83)，3.926(3.34)，3.947(3.28)，3.977(3.35)，3.992(9.35)，4.008(9.05)，4.024(3.07)，4.524(6.38)，4.532(6.45)，7.823(16.00)，7.878(1.79)，7.882(1.93)，7.895(2.60)，7.897(2.76)，7.910(1.89)，7.914(1.90)，8.458(6.68)，8.462(6.64)，8.666(2.02)，8.676(4.13)，8.685(2.11)。
Example 108
diamix-2- {3- [ (2, 2-difluorocyclopropyl) methoxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002091
N, N-diisopropylethylamine (200 μl,1.1 mmol) was added to diamix-3- [ (2, 2-difluorocyclopropyl) methoxy]Piperidine sulfate hydrochloride (185 mg, 568. Mu. Mol) in 5ml of dichloromethane and the mixture was stirred for 5 minutes, then N- [ (3, 5-difluoropyridin-2-yl) methyl-2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (100 mg, 284. Mu. Mol) and acetic acid (19. Mu.l, 340. Mu. Mol) were added to the mixture. The mixture was then stirred at room temperature. After 3 hours, sodium triacetoxyborohydride (90.2 mg, 426. Mu. Mol) was added to the mixture, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and Mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phases C and D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 10.0mg (purity 100%, 7% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.05min；MS(ESIpos)：m/z＝528[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.074(1.61)，1.091(1.50)，1.237(1.72)，1.251(1.61)，1.348(1.50)，1.367(1.61)，1.488(2.47)，1.548(1.93)，1.556(1.40)，1.568(1.83)，1.623(1.83)，1.764(3.97)，1.783(3.54)，1.907(2.58)，1.963(1.61)，1.982(2.79)，1.997(1.61)，2.098(1.83)，2.383(0.97)，2.422(1.29)，2.566(1.40)，2.611(0.86)，2.651(2.79)，2.942(2.04)，2.956(1.93)，3.023(2.79)，3.043(5.26)，3.063(2.79)，3.254(1.40)，3.260(0.64)，3.315(3.76)，3.322(3.97)，3.375(1.07)，3.391(2.58)，3.406(2.79)，3.423(1.40)，3.570(2.04)，3.581(1.93)，3.928(3.65)，3.950(3.44)，4.524(7.73)，4.532(7.84)，7.822(16.00)，7.879(1.93)，7.883(2.15)，7.897(3.22)，7.910(2.04)，7.914(2.04)，8.459(7.30)，8.462(7.41)，8.666(2.36)，8.675(4.83)，8.685(2.36)。
Example 109
rac-2- [3- (cyclobutoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002101
N, N-diisopropylethylamine (200. Mu.l, 1.1 mmol) and acetic acid (19. Mu.l, 340. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (100 mg, 284. Mu. Mol) and rac-3- (cyclobutoxy) piperidine sulfate hydrochloride (164 mg, 568. Mu. Mol) in 5ml dichloromethane and the mixture was stirred at room temperature for 5 hours. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426. Mu. Mol) was added, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and Mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phases C and D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 10.0mg (purity 100%, 7% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.04min；MS(ESIpos)：m/z＝492[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.034(0.72)，1.046(1.63)，1.069(1.63)，1.083(0.81)，1.091(0.68)，1.311(0.68)，1.333(1.54)，1.352(1.72)，1.372(1.08)，1.385(1.04)，1.390(1.58)，1.403(2.76)，1.407(1.72)，1.416(1.72)，1.420(3.07)，1.433(1.99)，1.438(2.26)，1.445(1.31)，1.458(2.98)，1.464(3.12)，1.478(3.30)，1.485(3.12)，1.498(1.45)，1.505(1.27)，1.550(0.90)，1.567(2.53)，1.585(2.71)，1.600(2.85)，1.623(1.76)，1.757(4.84)，1.777(6.37)，1.790(4.07)，1.810(3.30)，1.823(2.53)，1.838(1.76)，1.937(2.21)，1.953(3.66)，1.969(2.26)，2.046(1.49)，2.064(2.71)，2.079(1.54)，2.112(3.44)，2.120(3.39)，2.383(0.45)，2.422(0.59)，2.465(0.50)，2.611(0.54)，2.641(2.26)，2.651(1.94)，2.659(2.12)，2.864(2.08)，2.882(1.94)，3.019(2.89)，3.037(5.24)，3.057(2.94)，3.234(1.63)，3.243(2.12)，3.250(2.85)，3.257(3.12)，3.924(3.98)，3.946(3.84)，3.968(0.90)，3.980(2.71)，3.993(3.80)，4.005(2.62)，4.017(0.77)，4.523(7.73)，4.532(7.73)，7.823(16.00)，7.879(1.90)，7.882(2.08)，7.897(3.30)，7.910(1.99)，7.914(2.03)，8.459(7.28)，8.462(7.37)，8.666(2.44)，8.676(4.79)，8.685(2.44)。
Example 110
rac-2- {3- [ (3, 3-difluorocyclobutyl) oxy ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002111
N, N-diisopropylethylamine (200. Mu.l, 1.1 mmol) and acetic acid (19. Mu.l, 340. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- (4-Oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (100 mg, 284. Mu. Mol) and rac-3- [ (3, 3-difluorocyclobutyl) oxy]Piperidine sulfate hydrochloride (185 mg, 568. Mu. Mol) in 5ml dichloromethane and the mixture was stirred at room temperature for 5 hours. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426. Mu. Mol) was added, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and passed throughPurification by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection. Gradient curves: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and Mobile phase B from 15ml to 39ml,10 to 12min 0ml Mobile phase A and 70ml Mobile phase B. Mobile phases C and D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 30.0mg (purity 100%, 20% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.06min；MS(ESIpos)：m/z＝528[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.083(0.83)，1.097(2.04)，1.119(2.12)，1.134(0.94)，1.324(0.86)，1.344(1.99)，1.364(2.10)，1.384(0.88)，1.478(3.86)，1.498(4.08)，1.518(1.52)，1.621(2.46)，1.643(2.15)，1.757(5.57)，1.777(4.80)，1.853(2.32)，1.867(2.21)，2.003(2.54)，2.019(4.36)，2.035(2.65)，2.084(1.85)，2.100(3.42)，2.117(1.88)，2.422(2.26)，2.431(2.76)，2.441(2.59)，2.446(2.68)，2.451(2.73)，2.459(2.87)，2.468(2.12)，2.524(2.07)，2.561(1.68)，2.636(2.87)，2.654(2.79)，2.874(4.00)，2.884(5.49)，2.901(3.70)，3.019(3.59)，3.040(6.90)，3.061(3.56)，3.257(0.66)，3.265(0.69)，3.308(2.37)，3.317(2.76)，3.325(3.06)，3.331(2.48)，3.340(1.74)，3.929(5.08)，3.951(4.86)，4.101(2.37)，4.524(9.90)，4.533(9.74)，7.824(16.00)，7.882(2.21)，7.897(4.14)，7.914(2.18)，8.459(7.92)，8.462(8.17)，8.667(2.84)，8.677(5.71)，8.686(2.92)。
Example 111
diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-4-carboxamide
Figure BDA0004107514540002121
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride (70.9 mg, 259. Mu. Mol) were combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 78.0mg (purity 100%, 57% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.95min；MS(ESIpos)：m/z＝454[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.816(10.43)，0.823(12.35)，0.826(12.52)，0.834(10.93)，0.849(1.65)，0.869(0.67)，1.386(0.84)，1.406(1.13)，1.428(1.10)，1.448(0.90)，1.469(0.43)，1.497(0.61)，1.503(0.75)，1.514(0.75)，1.552(0.84)，1.572(2.20)，1.588(1.25)，1.594(1.45)，1.629(1.77)，1.649(1.68)，1.689(1.68)，1.706(1.97)，1.887(1.48)，1.896(1.86)，1.904(2.87)，1.917(2.26)，1.923(2.52)，1.938(1.57)，1.946(1.48)，1.958(0.55)，1.965(0.43)，2.175(1.28)，2.193(2.38)，2.210(1.19)，2.591(1.04)，2.596(1.01)，2.611(1.25)，2.650(1.25)，2.672(1.01)，2.838(3.19)，2.846(3.16)，3.105(1.42)，3.122(2.61)，3.126(2.52)，3.143(1.42)，3.213(2.09)，3.236(2.17)，3.262(0.78)，3.279(3.51)，3.302(2.87)，4.028(1.68)，4.049(1.59)，4.189(1.10)，4.210(2.03)，4.229(1.01)，4.578(7.30)，4.588(7.30)，5.065(2.26)，5.149(2.29)，7.373(16.00)，7.883(1.88)，7.887(2.00)，7.902(2.96)，7.915(1.88)，7.919(1.94)，8.452(7.65)，8.456(8.70)，8.467(4.12)，8.477(2.09)。
Example 112
diamix-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-oxazole-4-carboxamide
Figure BDA0004107514540002131
2-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-oxazole-4-carboxamide (100 mg, 314. Mu. Mol) and diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride (86.5 mg, 317. Mu. Mol) were combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100x30mm mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 81.0mg (purity 100%, 51% of theory) of the target compound.
LC-MS (method 1): r is R t ＝0.88min；MS(ESIpos)：m/z＝438[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.809(11.35)，0.817(14.02)，0.820(14.57)，0.827(12.10)，0.841(2.08)，0.862(0.75)，1.379(1.01)，1.398(1.40)，1.419(1.40)，1.440(1.11)，1.460(0.55)，1.505(0.91)，1.564(2.73)，1.586(1.85)，1.623(2.24)，1.644(4.13)，1.665(2.50)，1.864(1.53)，1.880(3.45)，1.889(3.32)，1.900(2.57)，1.906(2.57)，2.068(5.46)，2.160(1.56)，2.178(3.09)，2.197(1.63)，2.578(1.40)，2.615(1.46)，2.636(1.33)，2.824(4.33)，3.057(1.72)，3.075(3.28)，3.096(1.76)，3.181(2.67)，3.205(2.83)，3.246(2.83)，3.259(1.01)，3.271(3.77)，3.317(0.52)，4.085(2.37)，4.106(2.28)，4.130(1.63)，4.150(2.67)，4.173(1.46)，4.561(9.04)，4.570(9.01)，5.028(2.86)，5.111(2.89)，7.883(2.02)，7.887(2.05)，7.901(3.64)，7.915(2.05)，7.919(2.02)，8.004(16.00)，8.207(2.47)，8.217(4.81)，8.226(2.37)，8.459(7.93)，8.463(7.61)。
Example 113
diamix-N- (5-chloro-2-fluorobenzyl) -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002141
2-bromo-N- (5-chloro-2-fluorobenzyl) -1, 3-thiazole-5-carboxamide (100 mg, 286. Mu. Mol) and diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride (67.7 mg, 248. Mu. Mol) were combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D:acetonitrile/water (80% v/20% v) total flow rate: 80ml/min; room temperature; the wavelength is 200-400nm, and the sample is completely injected. Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 25.0mg (purity 97%, 18% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.17min；MS(ESIpos)：m/z＝469[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.809(11.21)，0.818(13.98)，0.820(14.09)，0.828(11.39)，0.843(2.02)，0.863(0.72)，1.122(0.47)，1.381(0.94)，1.401(1.30)，1.423(1.26)，1.443(1.08)，1.464(0.58)，1.496(0.90)，1.565(2.85)，1.587(1.84)，1.623(2.16)，1.645(2.09)，1.681(1.98)，1.699(2.38)，1.884(3.14)，1.892(3.71)，1.909(2.56)，1.927(0.58)，2.162(1.41)，2.180(2.70)，2.199(1.41)，2.384(0.43)，2.422(0.47)，2.607(1.37)，2.622(1.15)，2.665(1.15)，2.682(1.15)，2.823(4.07)，3.143(1.62)，3.160(3.03)，3.181(1.69)，3.241(2.59)，3.265(3.96)，3.307(3.14)，3.332(2.49)，3.411(0.86)，4.001(2.09)，4.024(1.98)，4.174(1.37)，4.195(2.34)，4.217(1.23)，4.405(10.20)，4.414(10.13)，5.058(2.77)，5.140(2.74)，7.231(3.17)，7.247(6.09)，7.262(3.96)，7.352(4.36)，7.362(6.56)，7.375(2.56)，7.382(2.45)，7.822(16.00)，8.713(2.52)，8.722(5.01)，8.732(2.56)。
Example 114
2- [ (3R) -3- (cyclopropylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002151
2-bromo-N- [ (3, 5-difluoropyridin-2-yl)) Methyl group]-1, 3-thiazole-5-carboxamide (80.2 mg, 240. Mu. Mol) and (3R) -3- (cyclopropylmethoxy) -1,4' -bipiperidine dihydrochloride (66.0 mg, 212. Mu. Mol) were combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100x30mm mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature, wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 46.0mg (purity 100%, 39% of theory) of the target compound.
LC-MS (method 1): rt=1.01 min; MS (ESIpos): m/z=492 [ m+h ]] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.116(2.25)，0.124(7.52)，0.131(7.71)，0.140(2.25)，0.411(2.21)，0.417(6.60)，0.420(6.38)，0.431(6.78)，0.433(6.27)，0.440(1.84)，0.915(0.77)，0.926(1.59)，0.937(2.32)，0.948(1.55)，1.023(0.59)，1.030(0.66)，1.044(1.59)，1.067(1.66)，1.080(0.77)，1.088(0.66)，1.320(0.70)，1.339(1.59)，1.359(1.62)，1.380(0.70)，1.455(1.11)，1.474(2.95)，1.486(2.40)，1.494(3.13)，1.514(1.25)，1.613(2.06)，1.636(1.73)，1.762(4.17)，1.781(3.65)，1.885(1.81)，1.900(1.73)，1.933(2.21)，1.949(3.69)，1.965(2.25)，2.067(1.51)，2.081(2.73)，2.099(1.47)，2.422(0.44)，2.521(1.73)，2.557(1.33)，2.652(2.54)，2.671(2.14)，2.943(2.18)，2.955(2.03)，3.021(2.80)，3.040(5.46)，3.060(2.88)，3.243(14.49)，3.255(14.56)，3.268(3.61)，3.320(0.81)，3.927(3.80)，3.946(3.61)，4.523(7.74)，4.532(7.71)，7.822(16.00)，7.878(1.92)，7.882(1.99)，7.895(3.17)，7.910(1.95)，7.914(1.92)，8.459(7.37)，8.462(7.12)，8.665(2.43)，8.675(4.83)，8.684(2.40)。
Example 115
ent-2- {3- [ (cyclopropylmethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002171
67mg of rac-2- {3- [ (cyclopropylmethoxy) methyl][1,4' -bipiperidines]-1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002172
Chiralpak AY-H,5 μm,250x 20mm; mobile phase a:60% n-heptane, mobile phase B:40% ethanol+0.2% diethylamine in B; the flow rate is 15ml/min; and (3) detecting the temperature of 55 ℃): 220 nm). The enantiomer with retention time of 8.062 min was collected (HPLC: column->
Figure BDA0004107514540002173
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; the temperature is 55 ℃; and (3) detection: 220 nm). The solvent was removed to give 30mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.07min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：-0.146(2.10)，-0.024(1.44)，-0.017(5.45)，-0.009(5.51)，0.275(1.55)，0.282(4.53)，0.285(4.49)，0.288(2.09)，0.295(4.69)，0.298(4.42)，0.305(1.34)，0.755(0.46)，0.773(1.01)，0.791(1.41)，0.794(1.44)，0.804(1.40)，0.807(1.47)，0.815(1.92)，0.823(1.00)，0.826(1.08)，0.835(0.50)，1.230(0.43)，1.249(1.00)，1.269(1.02)，1.290(0.76)，1.298(0.72)，1.310(1.42)，1.322(1.47)，1.330(2.10)，1.338(1.53)，1.350(1.51)，1.369(0.44)，1.433(1.41)，1.439(1.58)，1.451(2.33)，1.467(1.38)，1.566(1.12)，1.617(2.07)，1.623(2.07)，1.764(0.92)，1.781(1.55)，1.798(0.81)，1.965(0.79)，1.983(1.44)，2.000(0.76)，2.352(9.20)，2.355(11.79)，2.357(8.79)，2.369(1.29)，2.394(16.00)，2.580(1.15)，2.662(1.37)，2.678(1.31)，2.885(1.91)，2.904(3.60)，2.923(1.91)，3.026(9.38)，3.037(9.30)，3.053(1.05)，3.069(3.29)，3.080(5.47)，3.089(3.47)，3.095(1.22)，3.105(0.91)，3.143(10.67)，3.780(2.83)，3.801(2.66)，4.379(5.25)，4.388(5.22)，7.679(11.00)，7.732(1.28)，7.735(1.33)，7.748(2.15)，7.750(2.18)，7.763(1.30)，7.767(1.30)，8.313(4.95)，8.316(4.80)，8.520(1.64)，8.529(3.26)，8.538(1.62)。
Example 116
ent-2- {3- [ (cyclopropylmethoxy) methyl ] [1,4 '-bipiperidin ] -1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002181
67mg of rac-2- {3- [ (cyclopropylmethoxy) methyl][1,4' -bipiperidines]-1' -yl } -N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002182
Chiralpak AY-H,5 μm,250x 20mm; mobile phase a:60% n-heptane, mobile phase B:40% ethanol+0.2% diethylamine in B; the flow rate is 15ml/min; and (3) detecting the temperature of 55 ℃): 220 nm). The enantiomer with retention time 8.740 min was collected (HPLC: column +.>
Figure BDA0004107514540002183
Chiralpak AY-H5 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; the temperature is 55 ℃; and (3) detection: 220 nm). The solvent was removed to give 28mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.07min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：-0.146(2.11)，-0.024(0.87)，-0.017(3.12)，-0.015(3.03)，-0.009(3.17)，-0.007(3.10)，0.275(0.95)，0.282(2.68)，0.285(2.76)，0.288(1.22)，0.292(1.19)，0.295(2.78)，0.298(2.72)，0.305(0.83)，0.774(0.55)，0.791(0.83)，0.793(0.81)，0.804(0.78)，0.807(0.82)，0.815(1.19)，0.823(0.58)，0.826(0.62)，1.250(0.55)，1.270(0.56)，1.291(0.42)，1.298(0.41)，1.310(0.79)，1.322(0.82)，1.330(1.17)，1.338(0.85)，1.350(0.84)，1.452(1.28)，1.467(0.79)，1.567(0.60)，1.623(1.14)，1.766(0.43)，1.783(0.69)，1.984(0.68)，2.351(8.08)，2.354(10.97)，2.357(8.10)，2.369(0.63)，2.393(16.00)，2.581(0.58)，2.662(0.72)，2.679(0.68)，2.886(1.09)，2.904(2.03)，2.924(1.09)，3.026(5.94)，3.037(5.84)，3.054(0.64)，3.069(1.97)，3.081(3.29)，3.089(2.05)，3.095(0.72)，3.105(0.53)，3.141(15.73)，3.779(1.60)，3.801(1.51)，4.378(3.00)，4.387(2.96)，7.678(7.07)，7.732(0.80)，7.736(0.84)，7.749(1.21)，7.751(1.24)，7.764(0.81)，7.768(0.81)，8.312(3.04)，8.316(2.99)，8.519(0.96)，8.529(1.94)，8.538(0.95)。
Example 117
diamix-N- [1- (2, 5-difluorophenyl) ethyl ] -2- [ (3R) -3' -fluoro-3-methyl [1,4' -bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002191
rac-2-bromo-N- [1- (2, 5-difluorophenyl) ethyl]-1, 3-thiazole-5-carboxamide (145 mg, 4)18. Mu. Mol) and diamix- (3R) -3 '-fluoro-3-methyl-1, 4' -bipiperidine dihydrochloride (98.9 mg, 362. Mu. Mol) were combined and stirred at 120℃in 2ml sodium carbonate solution (2 ml,2.0M,4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min 23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 117mg (purity 100%, 60% of theory) of the target compound.
LC-MS (method 1): r is R t ＝1.18min；MS(ESIpos)：m/z＝467[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.808(6.23)，0.816(13.24)，0.826(12.53)，0.841(1.66)，0.861(0.65)，1.378(1.12)，1.398(1.48)，1.417(16.00)，1.429(15.57)，1.544(1.06)，1.563(2.56)，1.580(1.42)，1.585(1.64)，1.622(1.79)，1.643(1.71)，1.675(1.64)，1.693(1.97)，1.863(1.00)，1.872(2.46)，1.888(3.25)，1.905(2.33)，2.157(1.20)，2.176(2.36)，2.194(1.22)，2.617(1.14)，2.655(1.04)，2.676(1.00)，2.805(1.54)，2.820(3.23)，3.131(1.10)，3.153(2.11)，3.175(1.10)，3.232(1.60)，3.257(2.09)，3.322(1.73)，3.998(1.42)，4.018(1.34)，4.194(1.34)，5.053(2.25)，5.135(2.27)，5.228(0.55)，5.240(2.19)，5.251(3.23)，5.263(2.17)，5.276(0.51)，7.099(1.22)，7.113(2.42)，7.120(1.81)，7.127(1.62)，7.133(0.85)，7.195(1.64)，7.203(2.01)，7.211(4.14)，7.218(4.04)，7.226(2.84)，7.233(2.40)，7.902(11.61)，7.914(0.51)，8.535(3.76)，8.547(3.57)。
Example 118
4- (2-chlorophenyl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidine ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002201
N, N-diisopropylethylamine (250 μl,1.4 mmol) and propylphosphonic anhydride (280 μl,50% in ethyl acetate, 460 μmol) were added to a solution of 4- (2-chlorophenyl) -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid (150 mg,357 μmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (101 mg,464 μmol) in 4.8ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: total flow of acetonitrile/water (80% by volume/20% by volume: 80ml/min; room temperature, wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min from 39ml to 15ml and Mobile phase B from 31ml to 55ml,10 to 12min 0ml Mobile phase A and 70ml Mobile phase B. Mobile phases C and D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 19.0mg (purity 100%, 10% of theory) of the target compound.
LC-MS (method 5): r is R t ＝2.13min；MS(ESIpos)：m/z＝546[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.796(0.63)，0.819(15.20)，0.830(16.00)，0.850(0.61)，0.857(0.57)，1.377(0.51)，1.397(1.27)，1.418(1.39)，1.438(0.57)，1.485(0.85)，1.492(1.06)，1.505(2.64)，1.512(3.04)，1.525(3.40)，1.531(3.30)，1.544(1.54)，1.573(1.65)，1.595(1.35)，1.621(1.37)，1.642(1.31)，1.746(1.78)，1.763(3.06)，1.782(3.83)，1.806(2.62)，2.040(1.06)，2.055(1.90)，2.073(1.06)，2.423(0.40)，2.474(1.12)，2.740(1.75)，2.753(3.19)，2.770(1.50)，3.061(2.13)，3.078(3.80)，3.098(2.16)，3.258(0.53)，3.314(0.63)，3.319(0.53)，3.917(2.75)，3.939(2.62)，4.384(5.88)，4.392(5.81)，7.141(1.88)，7.149(3.80)，7.157(1.86)，7.393(1.10)，7.404(3.34)，7.417(3.30)，7.427(4.23)，7.430(5.09)，7.440(2.18)，7.443(1.73)，7.480(1.46)，7.484(1.25)，7.494(3.15)，7.497(2.71)，7.506(2.41)，7.508(2.30)，7.522(5.28)，7.535(2.37)，7.857(1.42)，7.861(1.52)，7.873(2.37)，7.877(2.47)，7.889(1.48)，7.893(1.52)，8.248(5.85)，8.252(5.81)。
Example 119
4-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002211
N, N-diisopropylethylamine (180 μl,1.0 mmol) and propylphosphonic anhydride (200 μl,50% in ethyl acetate, 330 μmol) were added to a solution of 4-bromo-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid (100 mg,258 μmol) and 1- (3, 5-difluoropyridin-2-yl) methylamine dihydrochloride (72.7 mg,335 μmol) in 4.0ml acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: total flow of acetonitrile/water (80% v/20%) 80ml/min; room temperature, wavelength 200-400nm, complete sample injection; gradient profile: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min from 39ml to 15ml and Mobile phase B from 31ml to 55ml,10 to 12min 0ml Mobile phase A and 70ml Mobile phase B. Mobile phases C and D were constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 24.0mg (purity 100%, 18% of theory) of the target compound.
LC-MS (method 5): r is R t ＝2.00min；MS(ESIneg)：m/z＝513[M-H]-.
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.785(0.48)，0.791(0.54)，0.805(1.48)，0.815(15.08)，0.826(16.00)，0.845(0.61)，0.851(0.50)，1.371(0.48)，1.391(1.23)，1.411(1.30)，1.425(0.40)，1.432(0.56)，1.458(0.71)，1.479(1.90)，1.495(2.41)，1.500(2.41)，1.512(1.82)，1.518(1.65)，1.529(0.94)，1.541(0.59)，1.567(1.57)，1.573(1.21)，1.583(0.96)，1.589(1.26)，1.617(1.28)，1.638(1.25)，1.737(1.80)，1.754(3.05)，1.772(3.93)，1.795(2.40)，2.035(1.03)，2.050(1.90)，2.054(1.86)，2.069(1.69)，2.482(1.21)，2.519(1.17)，2.722(1.72)，2.734(2.95)，2.751(1.42)，3.063(1.74)，3.068(2.05)，3.085(3.51)，3.088(3.41)，3.105(2.05)，3.110(1.76)，3.318(0.48)，3.876(2.18)，3.898(2.07)，4.591(5.46)，4.600(5.48)，7.911(1.44)，7.915(1.53)，7.928(2.03)，7.930(2.15)，7.943(1.48)，7.947(1.55)，8.178(1.69)，8.187(3.45)，8.196(1.71)，8.478(5.56)，8.482(5.54)。
Example 120
4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002221
2-bromo-4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (100 mg, 271. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (69.2 mg, 271. Mu. Mol) were combined and stirred in sodium carbonate solution (540. Mu.l, 2.0M,1.1 mmol) at 120℃for 1 hour, then the resulting solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gives 111mg (purity 100%, 87% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.96min；MS(ESIpos)：m/z＝470[M+H] + 。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：-0.149(0.48)，0.146(0.50)，0.773(0.60)，0.810(14.86)，0.826(16.00)，0.852(0.70)，0.862(0.57)，1.352(0.47)，1.383(1.15)，1.413(1.36)，1.443(1.27)，1.472(2.29)，1.495(2.91)，1.504(2.92)，1.522(2.00)，1.531(1.75)，1.560(1.89)，1.602(1.85)，1.641(1.32)，1.725(1.91)，1.751(3.63)，1.775(3.60)，1.797(2.47)，2.023(1.08)，2.046(1.94)，2.052(1.91)，2.074(1.10)，2.328(0.60)，2.367(0.85)，2.670(0.64)，2.674(0.49)，2.710(2.59)，2.719(2.45)，2.736(2.63)，3.055(2.04)，3.080(3.62)，3.111(2.12)，3.868(2.52)，3.900(2.37)，4.580(5.48)，4.593(5.48)，7.910(1.38)，7.916(1.50)，7.935(2.01)，7.938(2.12)，7.941(1.91)，7.957(1.46)，7.963(1.55)，8.146(1.68)，8.159(3.47)，8.173(1.63)，8.483(4.79)，8.489(4.63)。
Example 121
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-propyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002231
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (9.7. Mu.l, 170. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50 mg, 142. Mu. Mol) and rac-3-propylpiperidine (36.1 mg, 284. Mu. Mol) in 3ml of dichloromethane was stirred at room temperature for 6 hours. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213. Mu. Mol) was added, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m10030 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min from 39ml to 15ml and mobile phase B from 31ml to 55ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gives 9.00mg (purity 100%, 14% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.89min；MS(ESIpos)：m/z＝464[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.782(0.42)，0.796(0.99)，0.802(1.00)，0.815(1.07)，0.822(1.05)，0.834(7.50)，0.847(16.00)，0.859(8.04)，1.080(0.68)，1.091(0.99)，1.094(0.85)，1.103(1.64)，1.116(1.70)，1.128(1.13)，1.137(1.31)，1.152(1.62)，1.163(1.21)，1.174(0.77)，1.185(0.44)，1.249(0.74)，1.261(2.17)，1.274(3.33)，1.286(2.73)，1.298(1.24)，1.354(0.40)，1.374(1.15)，1.380(0.89)，1.393(1.72)，1.409(1.32)，1.414(1.31)，1.420(1.00)，1.426(0.70)，1.440(0.48)，1.448(0.57)，1.461(1.18)，1.470(1.54)，1.480(1.76)，1.490(1.64)，1.499(1.26)，1.509(0.64)，1.570(1.35)，1.575(1.08)，1.586(0.84)，1.591(1.10)，1.654(1.11)，1.659(1.08)，1.667(0.72)，1.675(1.11)，1.762(2.32)，1.778(3.07)，1.795(2.67)，1.813(1.30)，2.057(0.93)，2.072(1.64)，2.075(1.62)，2.090(0.89)，2.473(0.92)，2.479(0.63)，2.727(1.42)，2.743(2.48)，2.753(1.62)，3.021(1.72)，3.041(3.32)，3.062(1.72)，3.923(2.55)，3.944(2.45)，4.524(4.71)，4.533(4.70)，7.822(12.11)，7.878(1.31)，7.882(1.39)，7.894(1.90)，7.897(1.97)，7.909(1.32)，7.913(1.36)，8.458(5.03)，8.462(4.90)，8.663(1.52)，8.673(3.08)，8.683(1.51)。
Example 122
4-cyclopropyl-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002241
2-bromo-4-cyclopropyl-N- [ (3, 5-difluoropyridin-2-yl) methyl ]-1, 3-thiazole-5-carboxamide (100 mg, 267. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (68.2 mg, 267. Mu. Mol) were combined and stirred in sodium carbonate solution (530. Mu.l, 2.0M,1.1 mmol) at 120℃for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C185 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection. Gradient profile: mobile phase A0 to 2min 39ml, mobile phase B0 to 2min 31ml, mobile phase A2 to 10min from 39ml to 15ml and mobile phase B from 31ml to 55ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 80.0mg (purity 98%, 62% of theory) of the target compound.
LC-MS (method 5): r is R t ＝2.11min；MS(ESIpos)：m/z＝476[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.787(0.64)，0.801(1.39)，0.812(15.16)，0.823(16.00)，0.834(1.40)，0.841(3.13)，0.846(4.94)，0.850(3.91)，0.855(2.63)，0.860(5.16)，0.868(3.30)，0.872(4.59)，0.876(4.88)，0.880(5.43)，0.884(3.26)，0.892(0.83)，1.366(0.47)，1.387(1.21)，1.407(1.28)，1.431(1.04)，1.444(2.03)，1.451(2.08)，1.464(2.21)，1.471(2.10)，1.485(1.20)，1.491(1.33)，1.502(0.89)，1.508(1.05)，1.519(1.03)，1.526(0.92)，1.564(1.52)，1.580(0.92)，1.585(1.23)，1.615(1.25)，1.636(1.21)，1.733(1.89)，1.750(5.64)，1.768(3.44)，2.029(1.03)，2.044(1.84)，2.048(1.84)，2.063(1.02)，2.423(0.47)，2.442(1.04)，2.461(1.92)，2.479(1.09)，2.652(0.41)，2.715(1.59)，2.728(2.95)，2.746(1.40)，2.772(0.74)，2.781(1.42)，2.786(1.50)，2.794(2.41)，2.802(1.38)，2.807(1.33)，2.816(0.65)，2.974(1.92)，2.991(3.49)，3.012(1.96)，3.264(0.81)，3.321(0.75)，3.826(2.55)，3.847(2.41)，4.507(5.32)，4.516(5.29)，7.868(1.47)，7.872(1.67)，7.885(2.09)，7.887(2.23)，7.888(2.12)，7.900(1.60)，7.903(1.61)，7.955(1.67)，7.964(3.49)，7.973(1.71)，8.452(5.76)，8.455(5.74)。
Example 123
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002251
97mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- (3-ethoxy [1,4' -bipiperidine)]-1' -yl) -1, 3-thiazole-5-carboxamide the enantiomers were separated by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002252
ChiralpakID,5 μm,250x20mm; mobile phase a:40% n-heptane, mobile phase B:60% ethanol+0.2% diethylamine in B; the flow rate is 20ml/min; and (3) detecting at 50 ℃ and: 220 nm). The enantiomer with retention time 2.336 min was collected (HPLC: column +.>
Figure BDA0004107514540002253
ChiralpakID-33 μm, flow rate1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; and (3) detection: 220 nm). The solvent was removed to give 38mg (99% ee) of the title compound.
LC-MS (method 2): r is R t ＝0.52min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.060(8.60)，1.071(16.00)，1.083(8.26)，1.235(0.59)，1.346(1.07)，1.365(1.08)，1.478(2.05)，1.497(2.16)，1.615(1.29)，1.638(1.12)，1.765(2.83)，1.784(2.51)，1.886(1.30)，1.901(1.26)，1.943(0.94)，1.959(1.62)，1.975(0.96)，2.066(0.82)，2.084(1.44)，2.100(0.79)，2.422(0.44)，2.651(1.43)，2.936(1.37)，2.952(1.34)，3.024(2.23)，3.043(4.12)，3.061(2.16)，3.248(1.59)，3.263(1.29)，3.312(0.54)，3.431(1.22)，3.442(3.89)，3.453(5.34)，3.464(4.14)，3.476(1.31)，3.479(1.09)，3.929(2.79)，3.948(2.67)，4.524(6.31)，4.533(6.25)，7.824(13.37)，7.879(1.72)，7.882(1.81)，7.898(2.60)，7.910(1.70)，7.914(1.78)，8.459(6.60)，8.462(6.49)，8.666(1.78)，8.676(3.41)，8.685(1.73)。
Example 124
ent-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-ethoxy [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002261
97mg of rac-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- (3-ethoxy [1,4' -bipiperidine)]-1' -yl) -1, 3-thiazole-5-carboxamide the enantiomers were separated by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002262
Chiralpak ID,5 μm,250x 20mm; mobile phase a:40% n-heptane, mobile phase B:60% ethanol+0.2% diethylamine in B; the flow rate is 20ml/min; and (3) detecting at 50 ℃ and: 220 nm). CollectingEnantiomer with retention time 4.263 min (HPLC: column +.>
Figure BDA0004107514540002263
Chiralpak ID-33 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; and (3) detection: 220 nm). The solvent was removed to give 37mg (99% ee) of the title compound.
LC-MS (method 2): r is R t ＝0.52min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.858(0.50)，1.060(8.69)，1.072(16.00)，1.083(8.44)，1.236(1.50)，1.355(1.34)，1.366(1.33)，1.479(2.47)，1.498(2.65)，1.616(1.60)，1.767(3.37)，1.785(3.03)，1.888(1.68)，1.904(1.66)，1.960(1.76)，2.084(1.62)，2.611(0.50)，2.652(1.56)，2.939(1.58)，3.024(2.76)，3.044(5.20)，3.064(2.72)，3.251(2.20)，3.431(1.40)，3.443(4.13)，3.454(5.81)，3.465(4.31)，3.477(1.43)，3.930(3.48)，3.951(3.36)，4.524(8.10)，4.533(8.05)，7.824(12.08)，7.879(1.78)，7.882(1.96)，7.897(3.40)，7.910(1.75)，7.914(1.92)，8.459(7.08)，8.462(7.27)，8.667(2.01)，8.676(3.85)，8.685(1.99)。
Example 125
ent-2- [3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002271
60mg of rac-2- [3- (cyclobutylmethoxy) [1,4' -bipiperidine were reacted with]-1' -yl]-N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002272
Chiralpak IF,5 μm,250x 20mm; flow ofPhase A:100% ethanol +0.2% diethylamine; the flow rate is 18ml/min; and (3) detecting the temperature of 70 ℃): 220 nm). The enantiomer with retention time of 9.999 min was collected (HPLC: column +.>
Figure BDA0004107514540002273
Chiralpak IF 5 μm, flow 1ml/min; mobile phase a:100% ethanol +0.2% diethylamine; the temperature is 70 ℃; and (3) detection: 220 nm). The solvent was removed to give 28mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.17min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.040(2.07)，1.059(2.23)，1.146(0.91)，1.158(1.69)，1.171(1.07)，1.234(0.93)，1.341(2.06)，1.360(2.22)，1.478(3.96)，1.497(4.40)，1.615(2.66)，1.645(5.09)，1.661(6.44)，1.675(5.50)，1.690(2.56)，1.765(5.75)，1.784(6.56)，1.809(6.11)，1.824(6.18)，1.837(3.88)，1.856(1.91)，1.888(2.92)，1.904(2.89)，1.922(3.01)，1.936(6.49)，1.950(8.09)，2.081(3.01)，2.405(1.46)，2.418(3.03)，2.430(3.84)，2.442(3.00)，2.455(1.53)，2.654(3.03)，2.941(2.94)，2.954(2.67)，3.022(4.06)，3.041(7.67)，3.061(4.38)，3.225(3.06)，3.357(3.40)，3.373(7.35)，3.384(12.29)，3.396(7.41)，3.411(2.89)，3.929(5.35)，3.950(5.23)，4.523(11.02)，4.532(11.02)，7.823(16.00)，7.878(2.73)，7.895(4.72)，7.910(2.65)，8.458(9.67)，8.664(3.17)，8.674(5.69)，8.683(3.01)。
Example 126
ent-2- [3- (cyclobutylmethoxy) [1,4 '-bipiperidin ] -1' -yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002281
60mg of rac-2- [3- (cyclobutylmethoxy) [1,4' -bipiperidine were reacted with]-1' -yl]-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1The 3-thiazole-5-carboxamide is separated into the enantiomers by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002282
Chiralpak IF,5 μm,250x 20mm; mobile phase a:100% ethanol +0.2% diethylamine; the flow rate is 18ml/min; and (3) detecting the temperature of 70 ℃): 220 nm). The enantiomer with retention time 13.165 min was collected (HPLC: column +.>
Figure BDA0004107514540002283
Chiralpak IF 5 μm, flow 1ml/min; mobile phase a:100% ethanol +0.2% diethylamine; the temperature is 70 ℃; and (3) detection: 220 nm). The solvent was removed to give 28mg (99% ee) of the title compound.
LC-MS (method 1): r is R t ＝1.17min；MS(ESIpos)：m/z＝506[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.023(0.51)，1.037(1.19)，1.060(1.31)，1.078(0.73)，1.143(1.12)，1.155(2.25)，1.167(1.19)，1.235(0.77)，1.321(0.52)，1.341(1.20)，1.361(1.25)，1.381(0.56)，1.477(2.28)，1.497(2.44)，1.516(0.97)，1.614(1.60)，1.635(1.78)，1.647(2.81)，1.662(3.59)，1.677(2.98)，1.690(1.31)，1.766(3.39)，1.775(2.10)，1.785(3.78)，1.793(2.73)，1.800(2.08)，1.810(3.38)，1.815(1.70)，1.824(4.53)，1.829(1.22)，1.838(2.43)，1.842(1.48)，1.852(0.85)，1.857(0.97)，1.870(0.53)，1.889(1.42)，1.903(1.41)，1.923(1.61)，1.927(1.22)，1.932(1.92)，1.936(3.89)，1.945(3.31)，1.953(4.52)，1.956(4.37)，1.964(2.83)，1.970(2.58)，1.978(1.21)，2.065(1.01)，2.082(1.80)，2.099(0.98)，2.406(0.92)，2.418(1.98)，2.431(2.54)，2.443(1.88)，2.456(0.85)，2.564(0.87)，2.655(1.60)，2.672(1.48)，2.908(0.92)，2.921(0.98)，2.942(1.72)，2.955(1.58)，3.023(2.34)，3.042(4.41)，3.061(2.35)，3.210(1.08)，3.218(1.46)，3.225(1.90)，3.233(1.43)，3.242(1.19)，3.317(0.46)，3.357(1.62)，3.369(1.91)，3.373(5.39)，3.385(10.05)，3.396(5.32)，3.401(1.89)，3.412(1.57)，3.930(3.09)，3.950(2.94)，4.524(6.50)，4.533(6.41)，7.813(0.48)，7.824(16.00)，7.878(1.87)，7.882(1.93)，7.894(2.71)，7.897(2.72)，7.910(1.85)，7.913(1.87)，8.458(7.25)，8.462(6.95)，8.665(2.10)，8.675(4.20)，8.684(2.03)。
Example 127
Fac-carboxylic acid N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [3- (2-fluoroethyl) [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002291
N, N-diisopropylethylamine (49. Mu.l, 280. Mu. Mol) and acetic acid (9.7. Mu.l, 170. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (50 mg, 142. Mu. Mol) and rac-3- (2-fluoroethyl) piperidine (37.2 mg, 284. Mu. Mol) in 3ml of dichloromethane was stirred at room temperature for 6 hours. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213. Mu. Mol) was added, and the mixture was stirred at room temperature overnight. Adding saturated NaHCO 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and over Na 2 SO 4 And (5) drying. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and HPLC purified by preparative HPLC (instrument: waters Prep LC/MS system, column: phenomenex Kinetex C5 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection. Gradient profile: mobile phase A0 to 2min 63ml, mobile phase B0 to 2min 7ml, mobile phase A2 to 10min from 63ml to 39ml and mobile phase B from 7ml to 31ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 8.3mg (purity 90%, 62% of theory) of the target compound.
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.891(0.41)，0.908(0.96)，0.929(1.03)，0.943(0.48)，1.380(0.46)，1.401(1v07)，1.421(1.24)，1.440(0.58)，1.471(1.05)，1.485(2.38)，1.491(3.31)，1.504(2.79)，1.511(2.62)，1.524(1.89)，1.532(1.25)，1.542(0.86)，1.552(1.29)，1.562(1.40)，1.586(2.60)，1.592(3.22)，1.598(2.82)，1.609(2.29)，1.613(2.28)，1.620(2.03)，1.630(0.77)，1.681(1.29)，1.702(1.25)，1.774(3.02)，1.794(2.62)，1.901(1.30)，1.917(2.00)，1.934(1.18)，2.135(1.06)，2.150(1.91)，2.154(1.87)，2.168(1.12)，2.520(0.99)，2.564(1.18)，2.652(0.44)，2.735(1.56)，2.754(1.54)，2.781(1.79)，2.799(1.71)，3.028(2.21)，3.048(4.09)，3.068(2.26)，3.102(0.54)，3.480(1.58)，3.563(1.40)，3.934(3.17)，3.955(3.05)，4.430(1.61)，4.438(3.14)，4.448(1.87)，4.509(1.96)，4.519(4.42)，4.525(6.57)，4.533(5.92)，7.824(16.00)，7.865(0.74)，7.879(1.67)，7.883(1.74)，7.895(2.30)，7.898(2.39)，7.910(1.74)，7.914(1.69)，8.171(3.02)，8.459(6.28)，8.463(6.04)，8.668(1.79)，8.678(3.62)，8.687(1.72)。
Example 128
2- ([ 1,4 '-bipiperidin ] -1' -yl) -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002301
Acetic acid (9.7. Mu.l, 170. Mu. Mol) was added to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (100.0 mg, 284. Mu. Mol) and piperidine (56. Mu.l, 570. Mu. Mol) in 2ml of dichloromethane was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426. Mu. Mol) was added, and the mixture was stirred at room temperature overnight. Subsequently, saturated NaHCO is added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system,column: XBIdge C18 μm 100X30mm. Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80 vol%/20 vol%). Total flow rate: 80ml/min; room temperature; the wavelength is 200-400nm, and the sample is completely injected. Gradient curve: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 22.0mg (purity 100%, 18% of theory) of the title compound.
LC-MS (method 1): r is R t ＝0.80min；MS(ESIpos)：m/z＝422[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.366(3.44)，1.375(2.92)，1.444(1.06)，1.453(3.16)，1.463(7.91)，1.471(9.96)，1.482(6.13)，1.490(4.09)，1.504(1.17)，1.512(1.00)，1.769(3.09)，1.790(2.71)，2.430(5.90)，2.439(8.35)，2.447(6.39)，2.466(1.66)，2.471(2.35)，2.517(0.56)，2.651(0.41)，3.021(2.01)，3.025(2.37)，3.042(4.07)，3.045(4.08)，3.062(2.33)，3.067(2.09)，3.259(0.66)，3.920(3.18)，3.942(3.09)，4.523(5.69)，4.532(5.70)，7.821(16.00)，7.879(1.63)，7.882(1.78)，7.895(2.33)，7.897(2.41)，7.910(1.70)，7.914(1.76)，8.458(6.16)，8.462(6.16)，8.664(1.76)，8.673(3.62)，8.683(1.83)。
Example 129
N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002311
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (32.6 mg, 170. Mu. Mol), 1-hydroxy-1H-benzotriazole hydrate (26.0 mg, 170. Mu. Mol) and N, N-diisopropylethylamine (110. Mu.l, 650. Mu. Mol) were added to a solution of 2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxylic acid dihydrochloride (50.0 mg, 131. Mu. Mol) in 2ml of DMF and the mixture was stirred for 5 minutes, after which 1- (3, 5-difluoropyridin-2-yl) cyclopropylamine hydrochloride (1:1) (29.7 mg, 144. Mu. Mol) was added. The mixture was then stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC [ instrument: waters Prep LC/MS system, column: XBIdge C18 μm 100X30mm. Mobile phase a: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% v/20% v) total flow rate: 80ml/min; room temperature; the wavelength is 200-400nm, and the sample is completely injected. Gradient curve: mobile phase A0 to 2min 47ml, mobile phase B0 to 2min23ml, mobile phase A2 to 10min from 47ml to 23ml and mobile phase B from 23ml to 47ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 37.0mg (purity 100%, 61% of theory) of the title compound.
LC-MS (method 2): r is R t ＝0.56min；MS(ESIpos)：m/z＝462[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：0.782(0.51)，0.788(0.60)，0.812(15.17)，0.823(16.00)，0.842(0.59)，0.848(0.53)，0.955(0.47)，1.174(2.26)，1.182(6.55)，1.187(6.16)，1.194(2.43)，1.369(0.51)，1.389(1.31)，1.409(1.42)，1.429(0.62)，1.449(0.85)，1.464(2.23)，1.477(4.28)，1.484(9.56)，1.488(8.40)，1.496(3.72)，1.521(1.41)，1.527(1.17)，1.565(1.73)，1.581(1.06)，1.586(1.39)，1.615(1.46)，1.636(1.39)，1.737(1.83)，1.755(5.18)，1.772(2.86)，1.779(2.96)，2.036(1.15)，2.051(2.05)，2.070(1.12)，2.470(1.22)，2.720(1.75)，2.732(3.29)，2.748(1.72)，2.956(0.44)，3.020(2.17)，3.037(3.83)，3.058(2.15)，3.915(2.81)，3.936(2.67)，6.779(0.67)，6.785(0.65)，7.120(0.64)，7.125(0.60)，7.740(1.36)，7.744(1.44)，7.755(1.57)，7.759(2.67)，7.763(1.55)，7.774(1.38)，7.778(1.38)，7.835(11.84)，8.360(5.23)，8.364(4.87)，8.928(5.56)。
Example 130
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-ethyl-2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002321
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -4-ethyl-1, 3-thiazole-5-carboxamide (150 mg, 414. Mu. Mol) and (3R) -3-methyl-1, 4' -bipiperidine dihydrochloride (106 mg, 414. Mu. Mol) were combined and stirred in sodium carbonate solution (830. Mu.l, 2.0M,1.7 mmol) at 120℃for 1 hour. The reaction mixture was then purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBRID C18. Mu.m 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, gradient profile: mobile phase A0 to 2 minutes 39ml mobile phase B0 to 2 minutes 31ml mobile phase A2 to 10 minutes 39ml to 15ml and mobile phase B31 ml to 55ml,10 to 12 minutes 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D were constant flow rates of 5ml/min each over the entire run time). The product-containing fractions were combined and lyophilized. This gives 74.0mg (purity 100%, 39% of theory) of the target compound.
LC-MS (method 2): r is R t ＝0.60min；MS(ESIpos)：m/z＝464[M+H] + 。
1 H-NMR(500MHz，DMSO-d 6 )δ[ppm]：0.799(1.09)，0.813(11.56)，0.827(12.24)，0.847(0.47)，1.091(7.29)，1.106(16.00)，1.121(7.29)，1.388(0.88)，1.395(0.58)，1.412(0.97)，1.438(0.80)，1.447(0.69)，1.464(1.55)，1.472(1.65)，1.488(2.07)，1.495(2.07)，1.510(1.47)，1.521(1.26)，1.530(0.74)，1.544(0.47)，1.565(1.25)，1.571(0.94)，1.584(0.71)，1.591(0.92)，1.598(0.74)，1.615(0.99)，1.641(0.96)，1.733(1.37)，1.754(2.49)，1.774(2.92)，1.793(1.87)，2.029(0.79)，2.047(1.42)，2.052(1.39)，2.069(0.80)，2.453(0.77)，2.459(0.54)，2.469(0.96)，2.475(1.59)，2.482(1.28)，2.523(0.42)，2.727(1.39)，2.740(2.26)，2.760(1.12)，2.789(1.99)，2.804(6.09)，2.819(5.92)，2.834(1.81)，2.998(1.35)，3.003(1.59)，3.024(2.79)，3.028(2.70)，3.048(1.59)，3.891(2.15)，3.917(2.01)，4.488(4.13)，4.499(4.03)，7.879(1.35)，7.883(1.42)，7.897(1.69)，7.899(1.75)，7.901(1.82)，7.903(1.63)，7.917(1.34)，7.921(1.38)，7.989(1.38)，8.000(2.84)，8.011(1.31)，8.452(4.92)，8.456(4.69)。
Example 131
ent-2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 1)
Figure BDA0004107514540002331
60mg of rac-2- [4- (1, 1-difluoro-5-azaspiro [2.5] were reacted with]Oct-5-yl) piperidin-1-yl]-N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of the enantiomers of the 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002332
Chiralpak ID,5 μm,250x 20mm; mobile phase a:30% n-heptane, mobile phase B:70% ethanol+0.2% diethylamine in B; the flow rate is 20ml/min; and (3) detecting at 40 ℃ and: 220 nm). The enantiomer with retention time 1.927 min was collected (HPLC: column +.>
Figure BDA0004107514540002333
Chiralpak ID-33 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; and (3) detection: 220 nm). The solvent was removed to yield 23mg (98% ee) of the title compound.
LC-MS (method 5): r is R t ＝1.56min；MS(ESIpos)：m/z＝484[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.146(0.84)，1.158(2.52)，1.170(2.50)，1.186(1.37)，1.198(1.48)，1.215(2.36)，1.226(2.39)，1.436(0.92)，1.456(3.88)，1.476(8.04)，1.494(7.15)，1.603(2.19)，1.755(2.31)，1.776(4.13)，1.799(1.99)，2.377(2.43)，2.396(3.21)，2.422(2.44)，2.514(4.21)，2.568(1.52)，2.620(1.95)，3.046(3.16)，3.063(5.74)，3.083(3.23)，3.907(3.91)，3.926(3.72)，4.523(8.18)，4.532(8.18)，7.822(16.00)，7.878(1.98)，7.882(2.00)，7.897(3.37)，7.910(2.00)，7.913(1.97)，8.458(7.68)，8.461(7.29)，8.666(2.49)，8.676(4.92)，8.685(2.41)。
Example 132
ent-2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide (enantiomer 2)
Figure BDA0004107514540002341
60mg of rac-2- [4- (1, 1-difluoro-5-azaspiro [2.5] were reacted with]Oct-5-yl) piperidin-1-yl ]-N- [ (3, 5-difluoropyridin-2-yl) methyl]Separation of enantiomers of 1, 3-thiazole-5-carboxamide by chiral HPLC (preparative HPLC: column
Figure BDA0004107514540002342
Chiralpak ID,5 μm,250x 20mm; mobile phase a:30% n-heptane, mobile phase B:70% ethanol+0.2% diethylamine in B; the flow rate is 20ml/min; and (3) detecting at 40 ℃ and: 220 nm). The enantiomer with retention time 3.317 min was collected (HPLC: column +.>
Figure BDA0004107514540002343
Chiralpak ID-33 μm, flow rate 1ml/min; mobile phase a:50% n-heptane, mobile phase B:50% ethanol+0.2% diethylamine in B; and (3) detection: 220 nm). The solvent was removed to yield 23mg (99% ee) of the title compound.
LC-MS (method 5): r is R t ＝1.56min；MS(ESIpos)：m/z＝484[M+H] + 。
1 H-NMR(600MHz，DMSO-d 6 )δ[ppm]：1.146(0.75)，1.158(1.98)，1.171(1.91)，1.186(1.08)，1.198(1.15)，1.215(1.81)，1.227(1.85)，1.239(0.96)，1.436(0.80)，1.456(2.96)，1.477(5.97)，1.495(5.35)，1.522(1.38)，1.603(1.63)，1.613(1.24)，1.756(1.75)，1.780(3.00)，1.800(1.48)，2.377(1.82)，2.396(2.41)，2.422(1.92)，2.514(3.06)，2.568(1.08)，2.620(1.43)，2.651(0.41)，3.042(2.15)，3.046(2.46)，3.063(4.28)，3.083(2.49)，3.088(2.11)，3.906(2.87)，3.926(2.70)，4.523(6.11)，4.532(6.07)，7.822(16.00)，7.878(1.73)，7.882(1.81)，7.895(2.55)，7.897(2.67)，7.910(1.78)，7.914(1.86)，8.458(6.46)，8.461(6.36)，8.667(1.89)，8.676(3.89)，8.686(1.94)。
Example 133
rac-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- (3-phenyl [1,4 '-bipiperidin ] -1' -yl) -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002351
N, N-diisopropylethylamine (69. Mu.l, 400. Mu. Mol) and acetic acid (14. Mu.l, 240. Mu. Mol) were added sequentially to N- [ (3, 5-difluoropyridin-2-yl) methyl]A solution of 2- (4-oxopiperidin-1-yl) -1, 3-thiazole-5-carboxamide (70.0 mg, 199. Mu. Mol) and rac-3-phenylpiperidine (64.1 mg, 397. Mu. Mol) in 4.2ml of dichloromethane was prepared and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (63.2 mg, 298. Mu. Mol) was added, and the mixture was stirred at room temperature for 5 hours. Subsequently, saturated NaHCO is added 3 The solution was extracted with dichloromethane and the reaction mixture was extracted. The organic phase was washed with water and dried over Na2SO 4. The drying agent is filtered off and the filtrate is concentrated. The residue was dissolved in DMSO and HPLC was purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XB ridge C18 μm 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 8)0ml/min; room temperature; the wavelength is 200-400nm, and the sample is completely injected. Gradient curve: mobile phase A0 to 2min 70ml, mobile phase B0 to 2min 0ml, mobile phase A2 to 10min from 70ml to 0ml and mobile phase B from 0ml to 70ml,10 to 12min 0ml mobile phase a and 70ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5ml/min throughout the run time). The product-containing fractions were combined and lyophilized. This gives 17.0mg (purity 100%, 17% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.74min；MS(ESIpos)：m/z＝498[M+H] + 。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：-0.149(0.91)，0.146(0.77)，1.378(0.42)，1.400(1.08)，1.408(1.16)，1.430(1.35)，1.439(1.38)，1.461(1.11)，1.496(1.85)，1.510(2.16)，1.528(2.44)，1.560(1.50)，1.704(1.58)，1.736(1.16)，1.796(3.14)，1.819(2.95)，2.073(2.48)，2.157(1.25)，2.185(1.75)，2.201(1.77)，2.228(3.01)，2.255(1.62)，2.328(1.28)，2.367(1.69)，2.524(3.95)，2.574(2.01)，2.601(0.88)，2.666(1.83)，2.670(1.83)，2.693(1.57)，2.711(2.19)，2.856(2.82)，2.883(2.55)，3.015(1.85)，3.045(3.45)，3.075(1.89)，3.921(2.88)，3.954(2.64)，4.514(4.86)，4.527(4.95)，7.166(1.21)，7.172(0.84)，7.182(3.04)，7.193(1.08)，7.199(1.96)，7.204(1.62)，7.241(2.91)，7.257(12.12)，7.263(16.00)，7.280(6.40)，7.299(1.70)，7.820(15.56)，7.881(1.54)，7.887(1.58)，7.906(2.02)，7.910(2.10)，7.929(1.58)，7.935(1.60)，8.173(0.95)，8.460(4.70)，8.465(4.61)，8.685(1.67)，8.699(3.57)，8.713(1.70)。
Example 134
diamix-2- [4- (1, 1-difluoro-5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002361
2-bromo-N- [ (3, 5-difluoropyridine-2-) Radical) methyl radical]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and diamix-1, 1-difluoro-5- (3-fluoropiperidin-4-yl) -5-azaspiro [2.5]Octane dihydrochloride (96.1 mg, 299. Mu. Mol) was combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 30 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 46.0mg (purity 100%, 31% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.52min；MS(ESIpos)：m/z＝502[M+H] + 。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：-0.149(0.40)，1.174(2.35)，1.195(4.08)，1.216(2.33)，1.232(0.76)，1.462(1.17)，1.481(2.78)，1.501(4.70)，1.523(1.86)，1.608(1.52)，1.623(1.37)，1.668(1.19)，1.703(1.07)，1.846(0.95)，1.858(1.09)，1.879(1.18)，1.890(1.21)，1.911(0.72)，1.923(0.63)，2.328(0.44)，2.367(0.65)，2.524(3.86)，2.604(2.69)，2.633(1.49)，2.670(1.14)，2.699(2.14)，2.710(2.28)，2.769(0.60)，2.788(0.77)，3.126(1.00)，3.158(1.99)，3.190(1.15)，3.214(1.44)，3.250(1.52)，3.987(1.42)，4.019(1.34)，4.153(0.87)，4.187(1.56)，4.217(0.79)，4.521(5.39)，4.534(5.43)，5.026(1.17)，5.056(0.66)，5.149(1.18)，5.177(0.67)，7.812(16.00)，7.885(1.58)，7.891(1.73)，7.908(2.00)，7.910(2.18)，7.913(2.27)，7.916(2.13)，7.933(1.66)，7.938(1.74)，8.464(5.05)，8.470(5.00)，8.709(1.84)，8.724(3.89)，8.738(1.87)。
Example 135
diamix-2- [4- (5-azaspiro [2.5] oct-5-yl) -3-fluoropiperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide
Figure BDA0004107514540002371
2-bromo-N- [ (3, 5-difluoropyridin-2-yl) methyl]-1, 3-thiazole-5-carboxamide (100 mg, 299. Mu. Mol) and diamix-5- (3-fluoropiperidin-4-yl) -5-azaspiro [2.5]Octane dihydrochloride (85.4 mg, 299. Mu. Mol) was combined and stirred in 2ml of sodium carbonate solution (2 ml,2.0M,4 mmol) at 120℃for 30 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was taken up in Na 2 SO 4 Dried and filtered, and the filtrate concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: waters Prep LC/MS system, column: XBridge C18. Mu.m 100X30mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C:2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80ml/min; room temperature; wavelength 200-400nm, complete sample injection gradient profile: mobile phase A0 to 2min 55ml, mobile phase B0 to 2min 15ml, mobile phase A2 to 10min from 55ml to 31ml and mobile phase B from 15ml to 39ml,10 to 12min 0ml mobile phase A and 70ml mobile phase B. Mobile phase C and mobile phase D are constant flow rates of 5ml/min each over the whole run time). The product-containing fractions were combined and lyophilized. This gives 18.0mg (purity 100%, 13% of theory) of the target compound.
LC-MS (method 5): r is R t ＝1.52min；MS(ESIpos)：m/z＝466[M+H] + 。
1 H-NMR(400MHz，DMSO-d 6 )δ[ppm]：0.236(9.32)，0.259(7.85)，0.278(1.43)，0.294(0.46)，1.209(0.58)，1.227(1.61)，1.242(3.77)，1.257(3.72)，1.271(1.81)，1.290(0.55)，1.561(2.71)，1.571(3.44)，1.585(2.57)，1.669(1.21)，1.694(1.73)，1.787(0.48)，1.797(0.60)，1.818(1.34)，1.828(1.46)，1.849(1.31)，1.860(1.24)，1.880(0.46)，2.073(1.21)，2.269(1.36)，2.297(5.25)，2.313(4.36)，2.328(0.76)，2.339(1.10)，2.367(0.61)，2.577(4.23)，2.589(5.56)，2.602(3.30)，2.635(0.93)，2.644(0.90)，2.666(1.15)，2.710(0.57)，3.110(1.17)，3.136(2.08)，3.142(2.03)，3.167(1.24)，3.199(1.78)，3.235(2.02)，3.968(1.52)，4.001(1.41)，4.142(0.95)，4.172(1.62)，4.206(0.88)，4.520(5.56)，4.533(5.59)，5.026(1.83)，5.148(1.86)，7.810(16.00)，7.884(1.64)，7.890(1.76)，7.909(2.28)，7.913(2.39)，7.915(2.23)，7.932(1.72)，7.938(1.80)，8.164(0.74)，8.463(5.37)，8.469(5.31)，8.706(1.86)，8.720(3.88)，8.734(1.86)。
Analogously to examples 15 to 17, prepared from the starting materials described in each caseExamples 136 to 149The following compounds:
Figure BDA0004107514540002381
Figure BDA0004107514540002391
Figure BDA0004107514540002401
Figure BDA0004107514540002411
Figure BDA0004107514540002421
Figure BDA0004107514540002431
Figure BDA0004107514540002441
Figure BDA0004107514540002451
analogously to examples 18 to 22, prepared from the starting materials described in each caseExamples 150 to 152The following compounds:
Figure BDA0004107514540002452
Figure BDA0004107514540002461
B. evaluation of the pharmacological potency of the Compounds of formula (I)
The pharmacological activity of the compounds of formula (I) may be demonstrated by in vitro and in vivo studies, as known to those skilled in the art. The following examples of application describe the biological effects of the compounds of the invention and are not intended to limit the invention to these examples. Binding studies (B-1) and activity studies (B-2) were performed separately for in vitro characterization of receptor/substance interactions and determination of biological activity.
B-1 in vitro radioligand binding studies to determine the dissociation constant Ki of human adrenoreceptor ADRA2C (Eurofins Panlabs Discovery Services, taiwan, ltd)
Use is based on [ [ 3 H]A competition test of rauvollin as a radioligand to determine the binding affinity of the test substance at the human ADRA2C receptor.
To configure competition tests, radioligands were assayed in saturation experiments 3 H]The equilibrium dissociation constant Kd of rauvollin. For this purpose, CHO-K1 cells recombinantly expressing the human ADRA2C receptor were homogenized with increasing concentrations of radiolabel The agent was incubated in binding buffer (50 mM Tris-HCl,1mM EDTA,pH7.4) for 1 hour at 4 ℃. Nonspecific binding was determined by adding excess of the non-radiolabeled ligand prazosin (10 μm). Radioactivity was measured in a scintillation counter.
Under the above conditions, at 0.5nM [ 3 H]Competition experiments were performed in the presence of rauvolfia and increasing concentrations of the test substance to be characterized. The concentration of material that displaces 50% of the radiolabeled ligand is referred to as IC 50 Values.
From ICs measured in competition experiments 50 Values and Kd values from saturation experiments, using the Cheng Prusoff equation [ Cheng Y, prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50per centinhibition (I50) of an enzymatic reaction. Biochem Phacol. 22 (23): 3099-108.Doi:10.1016/0006-2952 (73) 90196-2.PMID 4202581 PMID:4202581]The equilibrium constant Ki of the inhibitor was calculated, which describes the affinity of the test substance for the receptor.
Equation 1
Figure BDA0004107514540002471
Cheng Prusoff equation. Ki = equilibrium constant of inhibitor, IC 50 Concentration of 50% of ligand displaced, kd=equilibrium constant of ligand, l=concentration of ligand
Table 1a below shows the binding affinity (Ki [ nM ]) for human ADRA2C receptor and the maximal half-inhibition (IC 50[ nM ]) of human ADRA2C receptor of representative embodiments of the present invention:
TABLE 1a
Figure BDA0004107514540002472
The data in table 1a show that the listed test substances bind to both human ADRA2C receptor and block the biological activity of human ADRA2C receptor. Thus, the results in table 1 demonstrate the mechanism of action of the compounds of the invention as ADRA2C inhibitors.
B-2.In vitro Activity assay to determine inhibition of recombinant ADRA2C
The human ADRA2C receptor belongs to the G protein (guanine-dependent protein) coupled receptor, whose main function is to transduce signals into the cell interior.
Co-expression of G with stable transfection αq The CHO-K1 cells of the protein and the calcium ion sensitive photoprotein aequorin were studied for inhibition of the recombinant human ADRA2C receptor. In this recombinant system, the binding of the agonist norepinephrine to the ADRA2C receptor causes calcium release from the intracellular pool (intracellular store) upon activation of the signaling cascade, which is detected as a bioluminescent signal by intracellular calcium sensing aequorin. The process is described in detail in the following references. [ Wunder F., [ Kalhof B., [ Muller T., [ Hueser J.functional Cell-Based Assays in Microliter Volumes for Ultra-High Throughput screening. Laboratory Chemistry ]&High Throughput Screening，Volume 11，Number 7，2008，pp.495-504(10).doi.org/10.2174/138620708785204054]
The activity of the test substances is determined by their ability to inhibit an agonist-induced increase in bioluminescence signal. The concentration that blocks half of the increase in the signal is called IC 50 . Computing IC using four-parameter logic function (hill function) 50 Value:
equation 2:hill function
Figure BDA0004107514540002481
Top = upper threshold, bottom = lower threshold, slope = Slope, IC 50 =turning point
Table 2 below lists the ICs determined for various embodiments of the invention from this test 50 Values (part is the average from multiple independent individual assays):
TABLE 2a
Figure BDA0004107514540002482
Figure BDA0004107514540002491
Figure BDA0004107514540002501
Figure BDA0004107514540002511
The data in table 2a show that the listed test substances block the biological activity of the human ADRA2C receptor. Thus, the results in table 1 confirm the mechanism of action of the compounds according to the invention as ADRA2C inhibitors.
B-3 animal model of obstructive sleep apnea in pigs
By using negative pressure, spontaneous breathing of anesthetized pigs can be caused by upper respiratory collapse and the resulting obstruction [ Wirth et al, sleep36，699-708(2013)]。
German Landress pigs were used for this model. Pigs were anesthetized and tracheae were dissected. One cannula each is inserted into the anterior and caudal portions of the trachea. The front cannula is connected to the means for generating negative pressure on the one hand and to the tail cannula on the other hand using a T-head. The tail cannula is connected to the front cannula and to a tube that allows spontaneous breathing by bypassing the upper respiratory tract using a T-connector. By properly closing and opening the tube, it is thereby possible for the pig to change from normal nasal breathing to breathing through the tail cannula when the upper respiratory tract is separated and connected to the means for generating negative pressure. The muscle activity of the genioglossus muscle was recorded by Electromyography (EMG).
At some point in time, the pigs were breathed by passing them through the tail cannula and applying-50, -100 and-150 cm of water (cm H) to the upper respiratory tract 2 O) and testing the collapse of the upper airway. Thereby collapsing the upper respiratory tract, which is manifested as a tube systemAir flow interruption and pressure drop in the system. The test is performed prior to administration of the test substance and at intervals after administration of the test substance. A suitably effective test substance may prevent collapse of the respiratory tract during this inspiration phase.
Administration of the test substance may be intranasal, intravenous, subcutaneous, intraperitoneal, intraduodenal or intragastric.
C.Experimental methods-binding of alpha 2-adrenoreceptor subtype C (alpha-2C) antagonists to TASK1/3 channel blockers Article (B)
The advantageous pharmacological properties of the combination of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist with a TASK1/3 channel blocker can be determined by the following method.
The therapeutic potential of the combination of an alpha 2-adrenoceptor subtype C (alpha-2C) antagonist according to the present invention with a TASK1/3 channel blocker in sleep apnea can be evaluated preclinically in a pig model of Obstructive Sleep Apnea (OSA).
By using negative pressure, spontaneous breathing of anesthetized pigs can be caused to collapse of the upper respiratory tract and the resulting obstruction (Wirth k.j. Et al., sleep 36 (5) (2013) pp.699-708).
German Landress pigs were used for this model. Pigs were anesthetized and tracheae were dissected. Two endotracheal tubes are inserted into the trachea, one into the anterior portion of the trachea (rostral part) and the other into the caudal portion of the trachea. The front cannula is connected to the tube leading to the negative pressure device and the distal endotracheal tube using a connector. The distal endotracheal tube is additionally connected to a tube having an open end to the atmosphere by a connector for free tracheal breathing, bypassing the upper airway. By properly opening and clamping the tubes, respiration can be switched from transnasal to through a tail tracheal tube, bypassing the upper respiratory tract, and the (separate) upper respiratory tract can be connected to a negative pressure device, creating an air flow in the direction of inspiration.
At some point in time, the collapsible upper respiratory tract was tested by breathing the pig through the tail cannula and applying negative pressure to the upper respiratory tract of-50, -100 and-150 cm of water column (cm H2O). Thereby collapsing the upper respiratory tract, which manifests itself as an interruption of air flow and a pressure drop in the tube system. The test is performed prior to administration of the test substance and at intervals after administration of the test substance. A suitably effective test substance may prevent collapse of the respiratory tract during this inspiration phase.
In this pig model of OSA, an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist of formula (I), such as N- [ (3, 5-difluoropyridin-2-yl) methyl, is applied systemically]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide is administered at 0.01mg/kg intraduodenally and only at 150 and 180 minutes time points after intraduodenally administration inhibits upper respiratory collapse in all pigs at all negative pressures of-50, -100 and-150 cm water column (cm H2O). At the time point 230 minutes post duodenal administration, all negative pressures at-50, -100 and-150 cm water column (cm H2O) induced upper airway collapse in all pigs. Such non-effective doses of the alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist N- [ (3, 5-difluoropyridin-2-yl) methyl of formula (I)]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) with an effective dose of a TASK1/TASK3 channel blocker]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Conjugates of octan-8-yl) methanones are present at-50, -100 and-150 cm of water (cm H) 2 O) inhibits the upper respiratory collapse for more than 3 hours (see tables 1,2 and 3 and fig. 1).
FIG. 1: 0.01mg/kg of the alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist N bis [ (3, 5-difluoropyridin-2-yl) methyl of formula (I) administered intraduodenally at time point 0 minutes]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide in combination with intranasal administration 0.3 μg TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) administered at a time point of 230 minutes after the start of the experiment]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octan-8-yl) methanone effect on upper respiratory collapse at different levels of negative pressure. The percentage of uncollapsed pigs is given. Average value.
Table 1:non-effective amounts of N- [ (3, 5-difluoro)Pyridin-2-yl) methyl]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) with an effective dose]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Conjugates of oct-8-yl) methanone at-50 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002541
Table 2:non-effective amounts of N- [ (3, 5-difluoropyridin-2-yl) methyl ]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) with an effective dose]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Conjugates of oct-8-yl) methanone at-100 cm water column (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002551
Table 3:non-effective amounts of N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) with an effective dose]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Conjugates of oct-8-yl) methanone at-150 cm water column (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002552
Figure BDA0004107514540002561
Tables 4, 5 and 6 and FIG. 2: at the position of0.3 μg of TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a) administered at the time point of 0 min]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Intranasal administration of oct-8-yl) methanone effects on upper respiratory collapse at different levels of negative pressure. The percentage of uncollapsed pigs is given. Average value.
Table 4:0.3 μg TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) at-50 cm of water column (cm H) 2 Intranasal administration of negative pressure of O)
Time, min Percentage of uncollapsed pigs-50 cm H 2 O，％
0 0
10 33
30 0
60 0
90 0
TABLE 5:0.3 μg of TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropyl)Phenyl) imidazo [1,2-a]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) at-100 cm of water column (cm H) 2 Intranasal administration of negative pressure of O)
Time, min Percentage of uncollapsed pigs-100 cm H 2 O，％
0 0
10 33
30 0
60 0
90 0
TABLE 6:0.3 μg TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1, 2-a)]Pyrimidin-3-yl]Methyl } -3, 8-diazabicyclo [3.2.1]Octyl-8-yl) at-150 cm water column (cm H) 2 Intranasal administration of negative pressure of O)
Time, min Percentage of uncollapsed pigs-150 cm H 2 O，％
0 0
10 0
30 0
60 0
90 0
In a second set of experiments, 0.01mg/kg of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist of formula (I), such as N- [ (3, 5-difluoropyridin-2-yl) methyl, was administered intraduodenally in the OSA pig model]-2- [ (3R) -3-methyl [1,4' -bipiperidine ]-1' -yl]Systemic use of 1, 3-thiazole-5-carboxamide no time point after intraduodenal administration was at-50, -100 and-150 cm water column (cm H) in all pigs 2 O) inhibits upper airway collapse. At the time point 90 minutes after intraduodenal administration, at negative pressure of-100 and-150 cm of water column (cm H) 2 O) induces collapse of the upper respiratory tract only at a negative pressure of-50 cm water column (cm H) 2 O) inhibits upper airway collapse. At a time point of 120 minutes after intraduodenal administration, at negative pressure of-150 cm of water column (cm H) 2 O) induces collapse of the upper respiratory tract at negative pressure of-50 and-100 cm water column (cm H) 2 O) inhibits upper airway collapse. At the time point 180 minutes after intraduodenal administration, all negative pressures at-50, -100 and-150 cm of water (cm H2O) induced upper airway collapse in all pigs. Such non-effective doses of alpha 2-adrenergic receptors of formula (I)N- [ (3, 5-difluoropyridin-2-yl) methyl as a subtype C (alpha-2C) antagonist]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a) with an effective dose of a TASK1/TASK3 channel blocker]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-50, -100 and-150 cm of water (cm H) 2 0) Is effective to inhibit upper airway collapse for 90 minutes (see tables 7, 8 and 9 and figure 3).
FIG. 3: 0.01mg/kg of the alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist N- [ (3, 5-difluoropyridin-2-yl) methyl of formula (I) administered 0 minutes at time point]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]Intraduodenal administration of 1, 3-thiazole-5-carboxamide in combination with 0.3 μg TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] administered at a time point 180 minutes after the start of the experiment]Pyridin-3-yl]Intranasal administration of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone effects on upper respiratory collapse at various levels of negative pressure. The percentage of uncollapsed pigs is given. Average value.
Table 7:non-effective amounts of N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-50 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002581
Table 8:non-effective amounts of N- [ (3, 5-difluoropyridin-2-yl) methyl ]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-100 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002591
Table 9:non-effective amounts of N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [ (3R) -3-methyl [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-150 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002592
Figure BDA0004107514540002601
In a third set of experiments, in this pig model of OSA, 15 μg/kg of an α2-adrenoreceptor subtype C (α -2C) antagonist of formula (I), such as ent-N- [ (3, 5-difluoropyridin-2-yl) methyl, was administered intravenously as a bolus]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]1, 3-thiazole-5-carboxamide, followed by systemic application at 5. Mu.g/kg/H for 4 hours in all pigs at-50, -100 and-150 cm of water column (cm H) at no time point after intravenous application 2 O) inhibits upper airway collapse. At a time point of 120 minutes after intravenous administration, a non-effective dose of TASK1/TASK3 channel blocker 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] was intranasally administered]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone. Such non-effective doses of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist of formula (I), e.g. ent-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a) with an effective dose of a TASK1/TASK3 channel blocker]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-50, -100 and-150 cm of water (cm) H 2 O) inhibits upper airway collapse for more than 4 hours (see tables 10, 11 and 12 and fig. 4).
FIG. 4: alpha 2-adrenoreceptor subtype C (alpha-2C) antagonists of formula (I), e.g. ent-N- [ (3, 5-difluoropyridin-2-yl) methyl, administered as a large dose at 15. Mu.g/kg followed by intravenous infusion at 5. Mu.g/kg/h for 4 hours at time point 0 minutes]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]Intravenous administration of 1, 3-thiazole-5-carboxamide was combined with 0.3 μg of TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] administered at a time point of 120 minutes after the start of the experiment ]Pyridin-3-yl]Intranasal administration of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone effects on upper respiratory collapse at various levels of negative pressure. The percentage of uncollapsed pigs is given. Average value.
Table 10:non-effective dose of ent-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-50 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002611
Table 11:non-effective dose of ent-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-100 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002612
Figure BDA0004107514540002621
Table 12:non-effective dose of ent-N- [ (3, 5-difluoropyridin-2-yl) methyl]-2- [3- (methoxymethyl) [1,4' -bipiperidine]-1' -yl]-1, 3-thiazole-5-carboxamide with a non-effective dose of 0.3 μg (4- { [2- (4-chlorophenyl) imidazo [1, 2-a) ]Pyridin-3-yl]Conjugates of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-150 cm of water (cm H) 2 Negative pressure inhibition of upper respiratory collapse of O)
Figure BDA0004107514540002622
Tables 13/14 and 15 and FIG. 5:0.3 μg of TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] administered at the time point of 0 min]Pyridin-3-yl]Intranasal administration of methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone effects on upper respiratory collapse at various levels of negative pressure. The percentage of uncollapsed pigs is given. Average value.
Table 13:0.3 μg TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-50 cm of water (cm H) 2 Intranasal administration of negative pressure of O)
Time, min Percentage of uncollapsed pigs-50 cm H 2 O，％
0 0
10 0
30 0
60 0
TABLE 14:0.3 μg TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-100 cm of water (cm H) 2 Intranasal administration of negative pressure of O)
Figure BDA0004107514540002631
TABLE 15:0.3 μg TASK1/TASK3 channel blocker (4- { [2- (4-chlorophenyl) imidazo [1, 2-a)]Pyridin-3-yl]Methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone at-150 cm of water (cm H) 2 Intranasal administration of negative pressure of O)
Time, min Percentage of uncollapsed pigs-150 cm H 2 O，％
0 0
10 0
30 0
60 0
From the above data, it can be deduced that the combination of an alpha 2-adrenoreceptor subtype C (alpha-2C) antagonist of formula (I) with a TASK1/3 channel blocker inhibits upper respiratory collapse with improved efficacy compared to each treatment alone and is therefore suitable for the treatment of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.

Claims (13)

1. Combinations of compounds of formula (I) and compounds of formula (II), and salts, solvates and solvates of salts thereof
Figure FDA0004107514530000011
Wherein the method comprises the steps of
X represents S, N or O;
y represents N, S or O, and the total number of the catalyst is,
wherein the method comprises the steps of
If X represents S, Y represents N;
z represents a group of compounds C, O, N,
wherein the method comprises the steps of
If X represents N and Y represents N, Z represents O;
R 1 represents a 5-or 6-membered heteroaryl or phenyl group,
wherein the 5-or 6-membered heteroaryl group may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -substituent substitution of alkoxy and halogen;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) The alkoxy groups may in turn be up to trisubstituted by halogen,
wherein the phenyl groups may be independently selected from 1 or 2 (C) 1 -C 4 ) -alkyl, (C) 3 -C 5 ) Cycloalkyl, (C) 1 -C 4 ) -substitution of substituents for alkoxy, cyano, hydroxy and halogen;
Wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 2 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
or (b)
And R is R 2 The carbon atoms to which they are attached together form (C 3 -C 4 ) A cycloalkyl ring, which is a ring-shaped member,
R 3 represents hydrogen or (C) 1 -C 4 ) -an alkyl group;
wherein (C) 1 -C 4 ) The alkyl groups may in turn be up to trisubstituted by halogen,
R 4 and is absent when Z represents N or O;
when Z represents C, it represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) -cycloalkyl, phenyl or halogen;
wherein (C) 1 -C 4 ) Alkyl may in turn be up to trisubstituted by halogen and phenyl may in turn be substituted by halogen,
R 5 represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -an alkoxy group or a halogen group,
R 6 a group of formula a), b), c), d), e), f) or g)
Figure FDA0004107514530000021
Wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 3 -C 4 ) Cycloalkyl, (C) 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) -a cyclic alkoxy group or a phenyl group,
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 3 -C 4 ) Cycloalkyl radicals、(C 1 -C 4 ) -alkoxy, (C) 3 -C 4 ) A cycloalkoxy group and may be up to trisubstituted by halogen,
wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl may in turn be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and may be up to two times by halogen,
Wherein (C) 1 -C 4 ) Alkoxy can in turn be substituted (C) 3 -C 4 ) Cycloalkyl and may be up to trisubstituted by halogen,
wherein (C) 3 -C 4 ) Cycloalkyl groups in turn may be mono-or di-substituted by halogen,
wherein (C) 3 -C 4 ) The cycloalkoxy groups may in turn be up to disubstituted by halogen,
wherein R is 8 Represents hydrogen or fluorine, and is preferably selected from the group consisting of,
wherein R is 9 Represents hydrogen, (C) 1 -C 4 ) -alkyl, (C) 1 -C 4 ) -alkoxy or halogen;
wherein (C) 1 -C 4 ) The alkyl radical may in turn be substituted (C) 1 -C 4 ) -an alkoxy group substituted by at least one amino group,
n represents 0 or 1, and the number of the n is,
m represents 0, 1 or 2,
p represents 0, 1 or 2
q represents 0, 1 or 2,
Figure FDA0004107514530000031
wherein the method comprises the steps of
Ring Q represents a piperazine or diazabicyclo system of the formula
Figure FDA0004107514530000032
Wherein is represented by CHR 'adjacent thereto' 2 The bond to which the group is attached and represents the bond to the carbonyl group,
W 1 、W 2 or W 3 Represents a group of compounds represented by CH or N,
R’ 1 represents halogen, cyano, (C) 1 -C 4 ) -alkyl, cyclopropyl or cyclobutyl
Wherein (C) 1 -C 4 ) Alkyl groups can be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl groups can be up to disubstituted by fluorine,
and
R’ 2 Representative (C) 4 -C 6 ) Cycloalkyl radicals, wherein ring CH 2 The group may be replaced by an-O-group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or (c) or pyrrolyl of the formula (d), (e), (f) or (g),
Figure FDA0004107514530000041
wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine, chlorine, bromine or methyl,
R’ 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
wherein (C) 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R’ 6 represents hydrogen, (C) 1 -C 3 ) -alkoxy, cyclobutoxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono- (C) 1 -C 3 ) -alkylamino, di- (C) 1 -C 3 ) -alkylamino or (C) 1 -C 3 ) -an alkylthio group, which is a group,
wherein (C) 1 -C 3 ) The alkoxy group may be up to trisubstituted by fluorine，
R 7 Represents hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl or (C) 1 -C 3 ) An alkoxy group, which is a group having a hydroxyl group,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, (C) 1 -C 3 ) -alkyl, cyclopropyl or (C) 1 -C 3 ) -alkoxy groups
Wherein (C) 1 -C 3 ) -alkyl and (C) 1 -C 3 ) Alkoxy groups can each be up to trisubstituted by fluorine,
R 9 represents hydrogen, (C) 1 -C 3 ) -alkyl or amino
and
Wherein in the sub-formula (d)
Y represents O, S or N (CH) 3 )，
Wherein in the sub-formulae (e) and (f)
Y represents O or S, and the like,
or (b)
R’ 2 represents-OR 10 or-NR 11 R 12 A group in which
R 10 Representative (C) 1 -C 6 ) -alkyl, (C) 4 -C 6 ) Cycloalkyl or [ (C) 3 -C 6 ) Cycloalkyl radicals]A methyl group,
R 11 represents hydrogen or (C) 1 -C 3 ) -alkyl group
and
R 12 Representative (C) 1 -C 6 ) -alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl or benzyl, 1-phenylethyl or 2-phenylethyl,
wherein (C) 1 -C 6 ) The alkyl group may be up to trisubstituted by fluorine,
and
Wherein phenyl and phenyl in benzyl, 1-phenylethyl and 2-phenylethyl may be up to trisubstituted by identical or different radicals from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl) thio,
Or (b)
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or
R 11 And R is 12 Are linked to each other and form together with the nitrogen atom to which they are attached a tetrahydroquinoline ring of formula (c) or a tetrahydroisoquinoline ring of formula (d),
Figure FDA0004107514530000051
wherein the bond to the carbonyl group is marked.
2. The combination of a compound of formula (I) and a compound of formula (II) as defined in claim 1, and salts, solvates and solvates of salts thereof
In the compounds of formula (I)
X, Y and Z are selected from S, N, O or C to form 1, 3-thiazolyl, 1, 3-oxazolyl or 1,2, 4-oxadiazolyl
R 1 Represents pyridyl, 2-ethylpyridyl, 4, 6-dimethylpyridyl, 3, 5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethylpyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 3-chlorophenyl, 1-chloro-1, 5-thienyl, 1-chloro-1-thiazolyl;
R 2 Represents hydrogen or methyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, methyl, ethyl or trifluoromethylA base;
R 5 represents hydrogen or fluorine, and is preferably selected from the group consisting of,
R 6 a group representing formula a), c') or c "),
Figure FDA0004107514530000061
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutyl-methoxymethyl 2, 2-trifluoroethoxy, 2-trifluoroethoxymethyl, 2-difluorocyclopropyl-methoxy cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy or fluorine;
n represents 0 or 1, and the number of the n is,
m represents a group of 1,
in the compounds of formula (II)
Ring Q represents a piperazine or diazabicyclo system of the formula
Figure FDA0004107514530000071
Wherein is represented by and adjacent CHR 2 Bond to a radical and represents bond to carbonyl
W 2 Represents a group of compounds which are represented by CH,
W 1 、W 3 represents a group of compounds represented by CH or N,
R’ 1 represents fluorine, chlorine, bromine, methyl, tert-butyl, isopropyl, cyclopropyl or cyclobutyl, and
R’ 2 represents a cyclobutyl, a cyclopentyl or a cyclohexyl group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d) or (g)
Figure FDA0004107514530000072
Wherein the bond linking adjacent carbonyl groups is marked
R’ 3 Represents hydrogen, fluorine or chlorine,
R’ 4 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R’ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutoxy or methylthio,
R 8A and R is 8B Identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
R 9 Represents methyl or amino groups
Y represents O or S or N (CH) 3 )。
3. The conjugate of claim 1 or 2, and salts, solvates and solvates of salts thereof, wherein
X, Y and Z are selected from S, N, O and C to form 1, 3-thiazolyl, 1, 3-oxazolyl or 1,2, 4-oxadiazolyl;
r1 represents pyridyl, 2-ethylpyridyl, 4, 6-dimethylpyridyl, 3, 5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethylpyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 1-thiazolyl, 5-chloro-1-thienyl;
R 2 Represents hydrogen or methyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, methyl, ethyl or trifluoromethyl;
wherein the phenyl group may in turn be substituted by chlorine,
R 5 represents hydrogen or fluorine, and is preferably selected from the group consisting of,
R 6 a group representing formula a), c') or c "),
Figure FDA0004107514530000091
wherein the bond to the adjacent piperidine ring is marked,
wherein R is 7 Or R's' 7 Independently of one another, represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutyl-methoxymethyl 2, 2-trifluoroethoxy, 2-trifluoroethoxymethyl, 2-difluorocyclopropyl-methoxy cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy or fluorine;
n represents 0 or 1, and the number of the n is,
m represents a group of 1,
in the compounds of formula (II)
Ring Q represents a diazabicyclo system of the formula
Figure FDA0004107514530000092
Wherein is represented by and adjacent CHR 2 The bond to which the radical is attached and represents the bond to the carbonyl group, W 1 Represents a group of compounds which are represented by CH,
W 2 represents a group of compounds which are represented by CH,
W 3 represents a group of compounds represented by the formula N,
R’ 1 represents chlorine, bromine, isopropyl or cyclobutyl,
and
R’ 2 Represents a cyclopentyl group or a cyclohexyl group, and is preferably a cyclohexyl group,
or (b)
R’ 2 Represents phenyl of the formula (a), pyridinyl of the formula (b) or pyrrolyl of the formula (d), (e) or (f)
Figure FDA0004107514530000101
Wherein the bond linking adjacent carbonyl groups is marked
R 4 Represents hydrogen, fluorine or chlorine,
R 5 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R 6 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 7 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutoxy or methylthio,
R 9A and R is 9B Identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
Y represents O or S.
4. The conjugate of claim 1, wherein said compound of formula (I) is selected from the group consisting of
N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 2-mono [4- (5-azaspiro [2.5] oct-5-yl) piperidin-1-yl ] -N- [ (3, 5-difluoropyridin-2-yl) methyl ] -1, 3-thiazole-5-carboxamide, N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3- (methoxymethyl) [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide, 4-chloro-N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4' -bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and N- [1- (3, 5-difluoropyridin-2-yl) cyclopropyl ] -2- [ (3R) -3-methyl ] -1, 4' -bipiperidin-5-carboxamide, 3-thiazole-5-carboxamide
And is also provided with
A compound of formula (II) selected from:
(4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, and (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [ 3.2.1-yl ] methanone.
5. The conjugate of claim 1, wherein the compound of formula (I) is N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide
And the compound of formula (II) is selected from:
(4- { [2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (cyclopentyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone, (4-mono { 2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (2-fluorophenyl) methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-isopropoxypyridin-2-yl) methanone, (4- { [2- (4-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (4- { [ 2-yl) imidazo [ 1-yl ] methyl } piperazin-1-yl ] (4- { [ 2-bromophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl), 2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) [6- (trifluoromethoxy) pyridin-2-yl ] methanone, (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, [5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-2-yl) methanone, [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxypyridin-3-yl) methanone, 2-a ] pyridin-3-yl ] methyl } hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] (6-methoxy-3-methylpyridin-2-yl) methanone, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl ] (6-methoxypyridin-2-yl) methanone, (-) - (3-chloro-6-methoxypyridin-2-yl) [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl ] methanone, (-) - [ (1S, 4S) -5- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2,5- { [ 2-dichloro-2-yl ] (2-chloro-6-methoxypyridin-2-yl) imidazo [1, 2-yl ] (2-chloro-1-chloro-2-yl) imidazo [ 2-1, 2-yl ] (2-chloro-2-fluoro) imidazo [ 2-yl ],1-2- { [ 2-methyl ], 2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone (-) - (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) (6-methoxypyridin-2-yl) methanone, (5- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) [6- (difluoromethoxy) pyridin-2-yl ] methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (5- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -2, 5-diazabicyclo [2.2.2] oct-2-yl) methanone, (3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-yl) methanone, 3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) methanone, 5- { [ 2-isopropyl ] imidazo [ 3.2.2.2 ] oct-yl ] methyl } -3-2-yl ] methanone (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-cyclopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone, 3- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -8-oxo-3, 10-diazabicyclo [3.2.1] oct-8-yl ] methyl } -3- { [ 2-fluoro-6-methoxypyridin-2-yl) methanone, 10-diazabicyclo [4.3.1] dec-10-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, [3- { [2- (5-chloropyridin-2-yl) imidazo [1,2-a ] pyridin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] non-9-yl ] (3-fluoro-6-methoxypyridin-2-yl) methanone, (3-fluoro-6-methoxypyridin-2-yl) [3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 9-diazabicyclo [4.2.1] nonan-9-yl ] methanone.
6. The conjugate of claim 1, wherein the compound of formula (I) is N- [ (3, 5-difluoropyridin-2-yl) methyl ] -2- [ (3R) -3-methyl [1,4 '-bipiperidin ] -1' -yl ] -1, 3-thiazole-5-carboxamide and the compound of formula (II) is (4- { [2- (4-chlorophenyl) imidazo [1,2-a ] pyridin-3-yl ] methyl } piperazin-1-yl) (6-methoxypyridin-2-yl) methanone or (3-chloro-6-methoxypyridin-2-yl) (3- { [2- (4-isopropylphenyl) imidazo [1,2-a ] pyrimidin-3-yl ] methyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) methanone.
7. A combination as defined in any one of claims 1 to 6 for use in a method of treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders.
8. Use of a combination as defined in any one of claims 1 for the preparation of a medicament for the treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders.
9. A medicament comprising a conjugate as defined in any one of claims 1 to 6 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.
10. A medicament comprising a conjugate as defined in any one of claims 1 to 6 in combination with one or more other active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.
11. A medicament according to claim 9 or 10 for the treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders.
12. A method of treatment and/or prophylaxis of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmune disorders in humans and animals by administration of an effective amount of at least one combination as defined in any of claims 1 to 6, or a medicament as defined in any of claims 9 to 11.
13. The use according to claim 7, wherein the sleep-related breathing disorders are obstructive and central sleep apnea and snoring.
CN202180054597.6A 2020-07-06 2021-07-05 Combinations of α2-adrenergic receptor subtype C (α-2C) antagonists and TASK1/3 channel blockers for the treatment of sleep apnea Pending CN116057057A (en)

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